Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH2:23]([C:25]1[C:29]([N+:30]([O-:32])=[O:31])=[C:28]([C:33]([NH2:35])=[O:34])[NH:27][N:26]=1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[C:25]([CH2:23][CH3:24])=[C:29]([N+:30]([O-:32])=[O:31])[C:28]([C:33]([NH2:35])=[O:34])=[N:27]2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 75 °C

Procedure:
1-Benzhydryl-3-azetidinyl methanesulfonate (8.03 g, 25.3 mmol, prepared according to the procedure in J. Org. Chem. 1991, 56, 6729-30) was added to a mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (4.64 g, 25.3 mmol, prepared using procedure in WO9849166) and cesium carbonate (8.24 g, 25.3 mmol) in MeCN (170 ml). The mixture was heated to 75° C. for 2 h and concentrated in vacuo. Water (200 ml) and EtOAc (200 ml) were added, and the mixture shaken. The insoluble solid at the interface was filtered off and dried to afford the title compound of preparation 52. The two layers of the filtrate were separated and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with EtOAc (50 ml) and the resultant solid was filtered off, washed with hot DCM/MeOH (90:10, 50 ml) and dried to afford more of the title compound of preparation 52. The liquors and washings were combined and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH, 98:2-95:5) to afford the title compound of preparation 51 plus a further small quantity of the title compound of preparation 52. The identity of the regioisomers was confirmed by nOe studies.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:32][C:33]([N:35]([CH3:46])[C:36]1[CH:45]=[CH:44][C:39]2[N:40]=[C:41]([CH3:43])[O:42][C:38]=2[CH:37]=1)=[O:34]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:32][C:33]([N:35]([CH3:46])[C:36]3[CH:45]=[CH:44][C:39]4[N:40]=[C:41]([CH3:43])[O:42][C:38]=4[CH:37]=3)=[O:34])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Reactant: COc1ccc2c(-c3cccc(F)c3)n[nH]c(=O)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A 0° C. solution of 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.0 g, 25.9 mmol) in THF (160 mL) was treated with LiHMDS (1M in THF) (38 mL, 38 mmol) and stirred for 30 min. 2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (7.33 g, 25.9 mmol) in THF (40 mL) was added dropwise and stirring was maintained at rt for 16 h. The reaction mixture was diluted with water (200 mL) and the product extracted with EtOAc (3×150 mL). The organics were washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude was triturated with MeOH (250 mL) to yield 2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (9.1 g, 74%). (472.87 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 2.62 (s, 3H), 3.33 (s, 3H), 4.95 (s, 3H), 4.73 (s, 2H), 7.37-7.43 (m, 4H), 7.48-7.51 (d, J=2.4, 8.8, 1H), 7.58-7.73 (m, 4H), 7.90 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:2]=2)=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: Nc1ccc(I)cn1
Reactant: COc1cc(C(=O)CBr)ccc1O
Solvent: CC#N
Product: COc1cc(-c2cn3cc(I)ccc3n2)ccc1O
Temperature: 110 °C
Yield: 31.4 %

Procedure:
490 mg (corresponding to 2.00 mmol) of 2-bromo-4′-hydroxy-3′-methoxyacetophenone and 440 mg (corresponding to 2.00 mmol) of 2-amino-5-iodopyridine were dissolved in 15 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 110° C. for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 3.0 mL of water and 1.0 mL of methanol. Then, about 6.0 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 231 mg (corresponding to 0.628 mmol) of 2-(4′-hydroxy-3′-methoxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 1, Step 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:34][C:28]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: Cc1ccc(C)c(C2CCCC(Br)C2=O)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(C)ccc2C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (72 mg, 0.27 mmol) and of crude 6-bromo-2-(2,5-dimethyl-phenyl)-cyclohexanone (81 mg, 0.29 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (11 mg, 9%) as an off-white solid. MS ISP (m/e): 445.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (s, 1H), 7.35 (s, 1H), 7.09 (d, 1H), 7.03 (d, 1H), 2.34 (s, (d, 1H), 6.82 (s, 1H), 6.69 (s, 1H), 6.62 (d, 1H), 4.21 (m, 1H), 3.53 (s, 3H), 2.78 (m, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.15 (m, 1H), 1.75-2.05 (m, 3H).
Reaction SMILES: [Na+].[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O-:22])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CC(N(C)C)=O>[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O:22][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (402 mg, 0.90 mmol) (obtained as described in Example 3) in dimethylacetamide (5 ml) was added iodomethyl pivalate (261 mg, 1.08 mmol) at 0° C. under an atmosphere of nitrogen and the mixture was stirred for 1 hour. At the end of this time, to the reaction mixture was added ethyl acetate and the organic layer was washed sequentially with 10% aqueous sodium chloride solution 10% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added diethyl ether to afford pivaloyloxymethyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (450 mg, yield 93%) as a colorless powder.
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#N.C(N(CC)CC)C>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH3:3])=[O:17]
Reactant: N#CCOC(=O)CCCC=Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCC=Cc1ccccn1
Yield: 115.3 %

Procedure:
To 6-(pyridin-2-yl)-5-hexenoic acid cyanomethyl ester (4.83 g, 21.0 mmol) was added methanol (50 ml) and triethylamine (0.405 g, 4.0 mmol) and the mixture was heated under reflux overnight and then evaporated to remove the solvent. The resultant residue was subjected to purification using column chromatography on silica gel to afford a target product, methyl 6-(pyridin-2-yl)-5-hexenoate (4.97 g, quantitative).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: Oc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cccc2c1CCCC2

Procedure:
5,6,7,8-Tetrahydronaphthalen-1-ol (Aldrich, 3.93 g, 26.5 mmol), propargyl bromide (80% in toluene, 3.9 ml, 35 mmol), and potassium carbonate (4.83 g, 35 mmol) were stirred together in acetonitrile (75 mL) for 6 days at ambient temperature. The solvent was removed under reduced pressure, and the residue taken into water and extracted with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.76 (m, 4H), 2.49 (t, J=2.37 Hz, 1H), 2.68 (t, J=5.59 Hz, 2H), 2.75 (t, J=5.59, 2H), 4.69 (d, J=2.37 Hz, 2H), 6.74 (dd, J=7.80, 3.73 Hz, 2H), 7.06 (t, J=7.80 Hz, 1H). MS (DCI) m/z 187.06 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[N:10]2[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of 0.28 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 6 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.50 g of 2-chloro-4-nitrobenzoyl chloride in 0.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour then quenched with 5 ml of saturated NaHCO3. The methylene chloride is evaporated in vacuo and the residue is diluted with 5 ml of water and extracted with 20 ml of ethyl acetate. The organic layer is separated, washed with saturated NAHCO3 and brine, dried with Na2SO4 and evaporated in vacuo to give 0.59 g of a yellow foam which is triturated with ether-hexanes to give 0.56 g of the desired product as off-white solid. MS(CI): 368(M+H)(Cl35); 370(M+H)(Cl37).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][S-:22].[Na+]>CN(C=O)C>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([S:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 110 °C
Yield: 51.8 %

Procedure:
A mixture of compound 6 (24.4 mg, 0.061 mmol) and sodium thiomethoxide (8 mg, 0.1 mmol) in DMF (1.5 mL) was heated for 22 h at 110° C. After cooling, the reaction mixture was concentrated to dryness and the residue was purified by a silica gel column chromatography (chloroform-methanol, 20:1) to give compound 16 (13 mg, 52.0%) as a colorless solid. 1H NMR (DMSO-d6) δ 3.06 (s, 6 H, N(CH3)2), 3.56 (s, 3 H, CH3), 4.58 (br s, 2 H, CH2), 7.10 (pseudo t, J=7.9 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.6 Hz, 1 H, H-17), 7.56 (d, J=7.9 Hz, 1 H, H-15), 7.76 (s, 1 H, H-13), 7.69 (s, 1 H, H-8), 7.90 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1.[H][H].[ClH:20]>CO.[OH-].[OH-].[Pd+2]>[ClH:20].[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[C:9]([F:15])[CH:8]=1
Reactant: COC(=O)[C@@H](C)COc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](C)COc1ccc(CN)c(F)c1
Yield: 95 %

Procedure:
(S)-3-(4-Cyano-3-fluoro-phenoxy)-2-methyl-propionic acid methyl ester (0.14 g) was shaken on a Parr shaker under 50 psi hydrogen for 16 h, using palladium hydroxide on carbon (0.01 g, 30% Pd by wt) in anhydrous methanol (20 mL) and concentrated hydrochloric acid (0.5 mL). The reaction mixture was filtered through sintered glass, and solvents removed in vacuo to afford 0.18 g of a white solid (95% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C@@H:5]2[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:4]1[C@H:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H]2CNCCN12
Yield: 134.2 %

Procedure:
To a cooled (0° C.) solution of (R)-tert-butyl 3-oxo-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.01 g, 12 mmol) in 100 mL CH2Cl2 was added TFA (75 mL, 973 mmol) dropwise. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2 to give 2.29 g of an orange oil. MS m/z: 143.1 [M+1].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30][C:29]2=[O:43])[O:4]1.[C:44]1(=[O:50])[O:49][C:47](=[O:48])[CH2:46][CH2:45]1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][N:28]([C@H:5]2[CH2:6][N:7]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][C@@H:3]([CH2:2][O:1][C:44](=[O:50])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])[O:4]2)[C:29](=[O:43])[N:30]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Nc1ccn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)n1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CCC(=O)OC[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Under argon atmosphere, 22.0 g of N-{1-[(2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}benzamide and 7.04 g of 4-dimethylaminopyridine (4-DMAP) were suspended in 269 mL of dichloromethane, and 5.76 g of succinic anhydride was added to the suspension, followed by stirring at room temperature for 3 hours. To the reaction solution was added 40 mL of methanol, and the mixture was concentrated under reduced pressure. The residue was extracted using ethyl acetate and 0.5M aqueous potassium dihydrogenphosphate solution. The resulting organic layer was washed sequentially with 0.5M aqueous potassium dihydrogenphosphate solution, water and brine in the order mentioned. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 25.9 g of the product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6](=[CH:9][C:10]([CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH3:11])[CH2:7][OH:8].C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:8][CH2:7][C:6]([F:5])=[CH:9][C:10]([CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][CH:13]=1)[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C=C(F)CO)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (0.41 ml), 2-fluoro-4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enol (Example 10) (0.2 g), benzene (10 ml) and pyridine (0.081 ml) to yield the title compound (0.23 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:25][CH:24]([CH3:26])[CH2:23][CH2:22][N:21]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: CC(C)CCNCCC(C)C
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N(CCC(C)C)CCC(C)C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and diisoamylamine (9.4 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.7 mg). Calcd for C21H30N2O2: 342.2307, found 342.2318.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29]4)[C:17]([C:34]([F:37])([F:36])[F:35])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:40][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4([C:31]([NH2:33])=[O:32])[CH2:29][CH2:30]4)[C:17]([C:34]([F:35])([F:37])[F:36])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2C(F)(F)F)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a mixture of 1-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 68 (0.069 g, 0.14 mmol) in anhydrous MeOH (2.0 mL) was added 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) and sodium triacetoxyborohydride (0.147 g, 0.695 mmol). The mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere and then quenched with sat. aq. NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organics were dried using a phase separation cartridge and concentrated in vacuo. Purification by prep-LCMS gave the title compound 69 (0.020 g, 29%) as the formic acid salt (2 equivs. determined by 1H NMR). LCMS-A: rt 4.802 min; m/z 525.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#N.F[B-](F)(F)F.[SiH](CC)(CC)CC.[OH2:26]>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])=[O:26]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: O
Agent: CC[SiH](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(C=O)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
A solution of 305 mg (1.74 mmol) of methyl 3-cyano-4-methylbenzoate and excess Et3O+BF4− in 7 mL of CH2Cl2 was stirred at 45° C. After 13 h and about 24 h more Et3O+BF4− was added and after a further 20 min. the temperature was increased to 50° C. After 37 h, the temperature was increased to 55° C. and heating was continued for 1.5 h. After this time, the crude solution was added with 3 mL of CH2Cl2 to 0.16 mL of Et3SiH in 5 mL of CH2Cl2. After the solution was stirred at 55° C. for 2 h, 10 mL of H2O was added, and the mixture was stirred at 120° C. for 15 min. and the temperature was decreased to 115° C. for 1 h, stopped for 2 h, and then resumed for 17 h. EtOAc was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (7.5% EtOAc/hexanes) provided 25 mg of methyl 3-formyl-4-methylbenzoate as colorless oil with some impurity. 5-(methoxycarbonyl)-2-methylbenzoic acid was synthesized from the aldehyde following the general procedure as described above for the methyl substituted benzoic acid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](=[CH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:38]3[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=3[F:36])[C:11]2=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1F)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 0.1 %

Procedure:
Under argon protection, E/Z 6-Chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 229c (8 g, 15.4 mmol) and 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30.8 mmol) were dissolved in toluene. The solution was heated at 80° C. for 5 h. Then the solution was concentrated and the residue was purified by chromatography (CH2Cl2:CH3OH=50:1) to obtain 1.7 g crude product. The crude product (50 mg) was purified again by Prep-HPLC to obtain give title compound as a white solid (12 mg).