Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
2.10 g (purity 74%, 4.72 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoic acid (racemate), 780 mg (4.72 mmol) of ethyl 4-aminobenzoate, 671 mg (4.72 mmol) of Oxima and 735 μl (4.72 mmol) of DIC in 47 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 263 ml of 10% strength lithium chloride solution and 210 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 210 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 2.1 g (75% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][CH2:8][O:9][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30](=[O:33])([O-])[O-:31].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:7][C:6]1[C:27]([C:2]2[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH2:7][CH2:8][OH:9])[CH:27]=2)=[CH:2][CH:3]=[CH:4][C:5]=1[C:30]([OH:31])=[O:33]
Reactant: COc1ccc(Br)cc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(C(=O)O)c2C)cc1CCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.013 g of [(5-bromo-2-methoxyphenethyl)oxy](t-butyl)diphenyl silane, 580 mg of 3-carboxymethylboronic acid, 170 mg of tetrakistriphenyl phosphine palladium and 1.01 g of potassium carbonate were dissolved in 12 ml of toluene, and the mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and then the residue was dissolved in 15 ml of tetrahydrofuran. To this reaction mixture was added 5 ml of tetrabutyl ammonium fluoride solution (1M) in tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by a silica gel column, and 197 mg methyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]benzoic acid was obtained from a fraction eluted with hexane-ethyl acetate (2:1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[SH:11][CH2:12][C:13]([OH:15])=[O:14]>[OH-].[K+].O>[F:10][C:7]1[CH:8]=[CH:9][C:2]2[S:11][C:12]([C:13]([OH:15])=[O:14])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=C(O)CS
Reactant: O=Cc1cc(F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cc(F)ccc2s1
Temperature: 125 °C
Yield: 80.1 %

Procedure:
In a glass pressure bottle, 2,5-difluorobenzaldehyde (11 ml, 0.1 mol) was added to a solution of 2-mercaptoacetic acid (9 ml) in potassium hydroxide (16.5 g) and water (155 ml). The bottle was then sealed and heated in a hot oil bath to 125±5° C. for 1.25 hours. The bottle was then removed from the hot oil bath and cooled. A pale yellow precipitate was obtained in the bottle. At ambient temperature, the bottle was opened and sufficient water was added to dissolve the precipitate. The resultant aqueous material was washed with ether and then acidified with hydrochloric acid to produce a pale yellow solid. The pale yellow solid was collected on a filter, washed with water and dried, to produce 15.5 g of 5-fluoro-2-benzo-[b]thiophenecarboxylic acid (80.1% yield, mp>300° C.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:33]CCl.Cl>C(O)C>[ClH:33].[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16](=[N:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The above ester (1.0 g, 3.0 mmol) was dissolved in ethanol (25 ml) and a 4 N sodium hydroxide solution (3.4 ml) was added. The mixture was stirred vigorously at room temperature for 22 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (75 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (1.6 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated three times with dichloromethane and once with acetone to give 0.95 g of the title compound as a foam.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1(C)C=CC=CC=1>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][N:29]=3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(-c2nccs2)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(-c2nccs2)c1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1, 178 mg, 0.45 mmol), 3-(1,3-thiazol-2-yl)phenol (162 mg, 0.91 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP, 217 μL, 0.75 mmol) in toluene (2 mL) was stirred at 110° C. for 5 h. After removal of solvent, the residue was eluted on silica gel short column (hexane/ethyl acetate (4/1)) to afford 259 mg (quant.) of the title compound as a white amorphous: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.7 Hz), 8.15–8.11 (2H, m), 7.97–7.94 (2H, m), 7.90–7.83 (3H, m), 7.58–7.38 (3H, m), 7.34–7.20 (2H, m), 5.42–5.32 (1H, m), 1.61–1.57 (12H, m); MS (ESI) m/z 536 (M+H)+, 534 (M−H)−.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][Si](C)(C)C)[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCO.C(Cl)Cl>[C:7]([C:3]1[CH:2]=[C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=1)#[CH:8]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCO
Product: C#Cc1cccc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (1,1′-biphenyl-3-ylethynyl)(trimethyl)silane (4.74 g, 18.96) in 1/1 EtOH/CH2Cl2 (60 mL) is added Cs2CO3 (6.78 g, 20.85 mmol) at room temperature. After stirring for 1 h, the insoluble material is filtered off and the filtrate is concentrated. The crude material is purified by chromatography (silica gel, 100% hexane) to give the title compound (3.07 g, 91%) as an oil. MS (+) EI: 178 M+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(O)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr
Temperature: 25 °C
Yield: 21.4 %

Procedure:
To a solution of 3-methylpicolinonitrile (700 mg, 5.93 mmol) in CCl4 (15 mL) was added recrystallized N-bromosuccinimide (1.21 g, 6.82 mmol), followed by glacial HOAc (0.34 mL, 1.0 eq), and AIBN (97 mg, 0.60 mmol). The resultant mixture was heated to 65° C. for 3 hours, 80° C. for 2 hours, and then cooled to room temperature. The mixture was filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by flash chromatography (Hexanes/EtOAc, 90:10 followed by 80:20) provided 3-bromomethyl-pyridine-2-carbonitrile (250 mg, 21%) as a white solid. 1H NMR(CDCl3) δ 4.63 (s, 2H), 7.55 (dd, 1H, J=8.0, 4.6 Hz), 7.93 (dd, 1H, J=7.9, 1.2 Hz), 8.64 (dd, 1H, J=4.8, 1.4 Hz).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-threonine methyl ester, hydrochloride (16.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-threonine methyl ester (21.5 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][C:3]1=[O:19].[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[O-])[CH3:21].[K+]>>[CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH2:20][CH3:21])[CH2:4][C:3]1=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2)cc1
Reactant: CCc1ccccc1[O-]
Agent: [K+]
Product: CCc1ccccc1OCC1CC(=O)N(C)C1

Procedure:
The compound is prepared from 1-methyl-4-tosyloxymethyl-pyrrolidin-2-one described in Example 17, and potassium 2-ethyl-phenoxide, as described in Example 17. B.p. (0.3 mm Hg)=186° C.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[F:31][C:32]1[CH:33]=[C:34]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C@H:45]3[CH2:50][CH2:49][C@H:48]([CH:51]=O)[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[F:38]>C1COCC1>[F:2][CH2:3][CH2:4][CH:5]=[CH:51][C@H:48]1[CH2:49][CH2:50][C@H:45]([C@H:42]2[CH2:43][CH2:44][C@H:39]([C:34]3[CH:35]=[CH:36][C:37]([F:38])=[C:32]([F:31])[CH:33]=3)[CH2:40][CH2:41]2)[CH2:46][CH2:47]1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: FCCC=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (13.8 g, 34.1 millimols) with THF (60 ml) was cooled down to -20° C., followed by adding t-BuOK (3.5 g, 34.1 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (120 ml) solution of trans-4-(trans-4-(3,4-difluorophenyl)cyclohexyl)cyclohexanecarbaldehyde (9.5 g, 31.0 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, to obtain raw (trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)-3,4-difluorobenzene (9.2 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:41][O:42][C:43](=[O:44])[NH:45][C@@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[C:47](=[O:48])[NH:1][C@@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:3]([OH:33])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:20][C:21](=[O:22])[C@H:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.7 %

Procedure:
A solution containing the product from Example 92J (0.049 g, 0.090 mmol) in THF (1 mL) was treated with the product from Example 1F (0.018 g, 0.095 mmol), DEPBT (0.040 g, 0.133 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 3 days, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The reaction was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and 10% Na2CO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.047 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79(s, 9H), 0.82(s, 9H), 1.58-1.43(m, 2H), 2.32(s, 3H), 2.79-2.68(m, 3H), 3.49(s, 3H), 3.55(s, 3H), 3.67-3.59(m, 1H), 3.843.80(d, J=9.93 Hz, 1H), 3.92-3.89(d, J=9.93 Hz, 1H), 4.19-4.01(m, 2H), 4.87-4.85(d, J=5.88 Hz, 1H), 6.63-6.60(d, J=9.19 Hz, 1H), 6.81-6.77(d, J=9.56 Hz, 1H), 7.19-7.12(m, 5H), 7.56-7.53(d, J=8.82 Hz, 1H), 7.68-7.64(m, 1H), 7.81-7.76(m, 3H), 7.86-7.83(d, J=8.09 Hz, 2H), 8.47(bs, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH3:18])[CH:8]=1.C[O:20][B:21](C)[O:22]C.Cl>CCCCCC.C1COCC1>[CH3:18][C:9]1[CH:8]=[C:7]([B:21]([OH:22])[OH:20])[CH:12]=[CH:11][C:10]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: COB(C)OC
Reactant: Cc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 8.5 ml (1.4 g, 21.1 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 4.9 g (19.2 mmol) of 4-bromo-2-methyl(trifluoromethoxy)benzene were dissolved in 15 ml of THF and slowly added dropwise. 3.0 g (28.8 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 3.3 g (78% of theory)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:34]=[C:22]1[CH2:23][C:24]([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4nccs4)cc3NC(=O)C2)c1
Yield: 40.7 %

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiazol-2-ylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K11) (119 mg, 0.24 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (36 mg).
Reaction SMILES: O.O.[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11])[N:8]=1.N12CCN(CC1)CC2.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[S:27]>CC(N(C)C)=O>[CH2:29]([O:28][P:26]([O:11][C:10](=[O:12])/[C:9](/[C:7]1[N:8]=[C:4]([NH2:3])[S:5][CH:6]=1)=[N:13]\[O:14][C:15](=[O:17])[CH3:16])([O:31][CH2:32][CH3:33])=[S:27])[CH3:30]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC(C)=O)c1csc(N)n1
Temperature: -20 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of 134.9 g (Z)-(2-aminothiazol4-yl)-acetoxyiminoacetic acid dihydrate (508.6 mmol) and 570 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.09 mmol) in 1500 ml dimethylacetamide was added under argon 158 ml tributylamine (661 mmol). The yellowish solution was cooled to -20° C. and over 30 min was added dropwise 104 ml diethyl chlorothiophosphate (661 mmol). Stirring was continued at -20° C. for 3.5 h. The reaction was followed by HPLC. After 3 h, all starting material was consumed. The reaction mixture was allowed to warm up to 0° C. and over 1.0 h was added dropwise 2200 ml water. The precipitated product was filtered, washed with water and dissolved in 800 ml dichloromethane. The aqueous layer was back-extracted with 300 ml dichloromethane. The combined organic layers were dried over 70 g sodium sulfate and concentrated under reduced pressure until the product started to crystallize. The residual solution was cooled to 2° C. and 1200 ml n-hexane was added dropwise over 1 h. The resulting suspension was stirred for 1 h at 2° C. and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxythiophosphoryl ester was obtained as a white solid (166.9 g, yield=86%, mp 128-130° C. and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:36](Cl)=[O:37])[CH:31]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[C:13](=[O:29])[C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:36](=[O:37])[C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and m-toluoyl chloride (0.4 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (20 mL). The residue was dissolved in CH2Cl2 (80 mL), washed with H2O (30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (silica gel) to N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 dihydro-1H-isoindol-4-ylmethyl]-3-methyl-benzamide (0.5 g, 66%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.37 (s, 3H, CH3), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.94 (d, J=5.7 Hz, 2H, CH2), 5.14-5.21 (dd, J=5.4 and 12.7 Hz, 1H, CH), 7.37-7.41 (m, 2H, Ar), 7.72-7.86 (m, 5H, Ar), 9.10 (t, J=5.6 Hz, 1H, NH), 11.14 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.91, 21.98, 30.93, 38.30, 48.87, 121.82, 124.42, 127.10, 127.83, 128.24, 131.52, 131.98, 132.99, 133.92, 134.77, 137.64, 139.39, 166.71, 166.96, 167.53, 169.81, 172.73; Anal. calcd. for C22H19N3O5+0.04H2O: C, 65.06; H, 4.74; N, 10.35. Found: C, 64.75; H, 4.68; N, 10.02.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][C:26]([CH3:34])([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:27])[N:20]=[C:19]([Cl:35])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:35][C:19]1[NH:20][C:21]([NH:24][CH2:25][C:26]([CH3:34])([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:27])=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCC(C)(C)N2CCOCC2)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(CNc1[nH]c(Cl)nc(=NN)c1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a suspension of tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.578 g, 0.94 mmol) in MeOH (8 mL) was added 4M HCl in 1,4-dioxane (8 mL), and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude residue was treated with an aqueous K2CO3 extractive workup to provide 2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4(1H)-pyrimidinone hydrazone as a brown oil (0.249 g). LCMS: (M+H)+=319.2.
Reaction SMILES: C1([Li])C=CC=CC=1.C(NC(C)C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(OCC)C>[Si:22]([CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)Cc1cccnc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In a 500 ml 3 neck round bottomed flask stirring under N2 was charged 33.1 ml of 2M phenyl lithium, in 70/30 cyclohexane diethyl ether, (0.0662 moles, 1.0 eq.), to which 6.70 g of diisopropylamine (1.0 eq. 0.0662 moles) in 10 ml of diethylether was pipetted into the flask followed by rapid addition of 6.16 g of 3-picoline (1.0 eq., 0.066 moles) in 10 ml of diethylether and 10.0 g of tert-butyldimethylsilylchloride (1.0 eq., 0.0662 moles) in 10 ml diethyl ether. The temperature of the reaction was maintained below 35° C. with an ice bath during the additions. After 1 hour of stirring GLC indicated the reaction was complete. The reaction was quenched by adding 100 ml of water, extracted with 250 ml of diethylether and washed with 2×100 ml of water. The ether was dried over magnesium sulfate and concentrated to give 12.3 g of an orange oil. GLC indicated the crude mixture was 96% product. A 7.0 g portion was purified by flash chromatography with 1:4 ethyl acetate/hexane and afforded 3.8 g (48.7% yield based on chromatographic portion) of 3-(tert-butyldimethylsilyl)pyridine.