Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH2:21]([O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]2[N:43]=[C:39]([CH:36]3[CH2:38][CH2:37]3)[O:40][CH:41]=2)=[O:45])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1)[CH3:22]
Reactant: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
5-Amino-2-ethoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8c (58.3 mg, 0.12 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1 h (27.9 mg, 0.18 mmol, 150 mol %) and N,N-diisopropylethylamine (0.06 ml, 0.36 mmol, 300 mol %) were combined in N,N-dimethylformamide (3.0 ml) and HATU (69.3 mg, 0.18 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by reverse phase HPLC (methanol+0.1% formic acid/water) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-ethoxy-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8e (54.8 mg, 0.09 mmol, 73.3%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31](COC)[N:32]=4)[CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)(=O)C>CO>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][N:31]=[CH:30]4)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(C[C@@H](OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)C(=O)OC)cc(C)c2n1
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reaction time: 1 h

Procedure:
To a solution of (R)-1-methoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (1.20 g, 2.25 mmol) in methanol (20 mL) was added acetyl chloride (0.40 mL, 5.62 mmol). The reaction was warmed to reflux and held there for 1 h. The reaction was concentrated by rotary evaporation under high vacuum and purified by column chromatography (5% methanol/dichloromethane) to give 1.09 g (99%) as a white foam solid. Mass spec.: 489.29 (MH)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[CH:11])[CH2:6][CH2:5]1.[CH2:14]([CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH:26]=[O:27])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1>[CH3:1][Si:2]([CH3:12])([CH3:13])[O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[C:11][CH:26]([OH:27])[CH2:25][CH:22]2[CH2:23][CH2:24][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21]2)[CH2:6][CH2:5]1
Reactant: CCCCCC1CCC(CC=O)CC1
Reactant: C#CC1CCC(O[Si](C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1CCC(CC(O)C#CC2CCC(O[Si](C)(C)C)CC2)CC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
4-Trimethylsilyloxycyclohexylacetylene (20 mmol) was dissolved in THF (20 ml), followed by dropwise adding a n-butyllithium-hexane solution (1.61M, 12.4 ml) while stirring the above solution under ice cooling, stirring the reaction solution under ice cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (4.0 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring it for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting the mixture with ethyl acetate (150 ml), washing the organic phase with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, which is recrystallized from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-trimethylsilyloxycyclohexyl)-4-(4-pentylcyclohexyl)-1-butyn-3-ol (5.0 g) (white crystal).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22]C)[CH3:20].ClC(OC1C=CC=CC=1)=[O:28].N1CCCC1>O1CCCC1.[Cl-].[NH4+].ClCCl>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:22]([N:21]2[CH2:24][CH2:25][CH2:20][CH2:19]2)=[O:28])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCC1
Yield: 43.2 %

Procedure:
6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (0.550 g, 2.2 mmol) was dissolved in tetrahydrofuran (10 ml). Then triethylamine (0.61 ml, 4.4 mmol) was added to the mixture with stirring. Then phenyl chloroformate (0.55 ml, 4.4 mmol) was added slowly to the mixture. The mixture was stirred at ambient temperature for 1.5 hours. Then pyrrolidine (1.8 ml, 22 mmol) was added to the mixture, and the mixture was stirred an additional 30 minutes. The mixture was diluted with sat. ammonium chloride and dichloromethane and stirred an additional 10 minutes. The organic layer was collected by extracting with dichloromethane (3×10 ml). Combined organic layer was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified by chromatography (Amino-Propyl silica gel column) in a gradient of 1-5% MeOH/dichloromethane to give an oil. The oil was recrystallized from dichloromethane/hexanes to give the desired product N-(6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl)pyrrolidine-1-carboxamide (0.330 g, 0.95 mmol, 43% yield) as a yellow solid. MS (ESI pos. ion) m/z: 348 (MH+). Calc'd exact mass for C15H14FN5O4: 347. 1NMR (300 MHz, CDCl3): 1.94 (s, 4H), 3.37-3.49 (m, 4H), 5.23 (s, 1H), 7.09-7.21 (m, 1H), 7.29-7.38 (m, 1H), 7.99-8.09 (m, 2H), 8.25 (d, J=0.73 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].[C:34](#[N:37])[CH:35]=[CH2:36]>C1(C)C=CC=CC=1>[C:34]([CH2:35][CH2:36][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])=[CH:19][CH:20]=2)[CH2:25]1)#[N:37]
Reactant: C=CC#N
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(CCC#N)CC4)c2)cc1OC
Temperature: 80 °C
Yield: 68.2 %

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 3 mL of toluene and added acrylonitrile (0.04 mL, 0.600 mmol). The mixture was heated at 80° C. for 2 h. LC-MS indicated the desired material. Concentrated to dryness and applied to a SiO2 prep plate. Eluted with (5% MeOH/1% NH3/CH2Cl2) to give 40.8 mg of N-{3-[2-(2-Cyano-ethyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-benzyl}-3,4-dimethoxy-benzamide. MS, electrospray 499.5 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[CH2:19]([NH2:22])[C:20]#[CH:21].O>O1CCOCC1>[CH2:19]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:20]#[CH:21]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: C#CCNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a stirred solution of 15.0 grams (0.094 mole) of 2,5-difluoronitrobenzene in 250 mL of dioxane was added 100 mL of triethylamine, followed by 7.3 grams (0.132 mole) of 2-propyn-1-ylamine. The reaction mixture was then warmed to reflux, where it was stirred for about four hours, then cooled to ambient temperature and poured into cold water. The resultant solid precipitate was collected by filtration and dried, yielding 10.0 grams of N-(2-propyn-1-yl)-4-fluoro-2-nitroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1>>[N:12]1([CH:3]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[C:4]([CH3:8])([CH3:5])[CH2:31][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc(F)cc(F)c1
Reactant: c1ccc2[nH]nnc2c1
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1cc(F)cc(F)c1)n1nnc2ccccc21

Procedure:
3,5-Difluorobenzamide, the product from Example 18A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: Nc1ccccc1
Reactant: COC(=O)CCCCCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CCCCCNc1ccccc1
Temperature: 0 °C

Procedure:
Aniline (2.79 g, 2.73 ml), 6.27 g of methyl 6-bromohexanoate and 12.24 g (0.09 mole) of sodium acetate trihydrate are heated at 80°-100° overnight in 15 ml of absolute ethanol. After cooling, the mixture is poured into 75 ml of ice-water and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo to give N-(5-methoxycarbonylpentyl)aniline.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:8]=[C:7]([CH3:20])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:37][CH2:38][CH3:39])[C:31]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)[CH:27]=O)[CH3:22].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:37][CH2:38][CH3:39])[C:31]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)[CH2:27][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[C:2]([CH3:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:20])[CH:8]=2)[CH2:19][CH2:18]1)[CH3:22]
Reactant: Cc1cc(C(=O)NC2CCNCC2)cc(C)c1C(=O)O
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)c(C(=O)O)c(C)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 2,6-dimethyl-N-piperidin-4-yl-terephthalamic acid (example 126b) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 520.3 (MH+).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br-].[CH2:8]([O:10][C:11]([CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])[CH3:9].[CH3:33][O:34][C:35]1[C:54]([O:55][CH3:56])=[CH:53][C:38]2[S:39][C:40](C=O)=[C:41]([O:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[CH:36]=1.Cl>O1CCCC1>[CH3:33][O:34][C:35]1[C:54]([O:55][CH3:56])=[CH:53][C:38]2[S:39][C:40](/[CH:1]=[CH:13]/[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[C:41]([O:42][C:43]3[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=3)[C:37]=2[CH:36]=1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1
Reaction time: 12 h

Procedure:
20 ml of a 1M solution of potassium tert-butylate in tetrahydrofuran are added dropwise at 0° C. under an inert atmosphere to a suspension of 0.02 mol of (ethoxycarbonylmethyl)triphenylphosphonium bromide in 90 ml of tetrahydrofuran. After the addition is complete and the mixture has returned to room temperature, 0.01 mol of the compound obtained in Step E of Example 1 diluted in 30 ml of tetrahydrofuran is added. After 12 hours, the reaction mixture is hydrolysed by the addition of 100 ml of a 1N HCl solution, and then extracted with ethyl acetate; the combined organic phases are washed with water and then with a saturated NaCl solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (pentane/ethyl acetate: 90/10) enables 2.78 g of the expected product to be isolated.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[OH2:32].C(N(CC)CC)C>C(#N)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[OH:19])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:32])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@H]1OC(=O)/C(=C\O)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17-hydroxy-wortmannin (20 mg, 0.047 mmol) is dissolved in 4 mL acetonitrile and 2 mL water with 0.5 mL triethylamine. The reaction mixture is stirred at room temperature overnight. The title compound is isolated by preparative HPLC using Nova-Pak HRC 18, 60A, 6 um, 19×300 mm column (Waters) at UV 254 nm (Mobile Phase A is 100 ml acetonitrile with 900 ml water, and 0.2 ml trifluoroacetic acid. Mobile Phase B is 900 ml acetonitrile with 100 ml water and 0.2 ml trifluoroacetic acid. The gradient is 0-5 min at 20% B and 80% A, 5-35 min from 20% B to 70% B at flow rate 20 mL/min). The fraction at 12 min peak is collected and extracted with CH2Cl2. The organic layer is dried over anhydrous sodium sulfate and rotavaped to dryness. A total of 5 mg of yellow solid is obtained by precipitation from 1 mL CH2Cl2 and 3 mL heptane and drying using nitrogen gas and then a speecdvac. LC/MS shows [M+H] 449.31 and [M−H] 447.26.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9](=[CH:13][O:14][CH2:15][CH3:16])[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH3:25])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:9]2[C@H:13]([O:14][CH2:15][CH3:16])[C@H:24]([CH3:25])[C:23]([O:26][CH2:27][CH3:28])([O:22][CH2:20][CH3:21])[O:12][C:10]=2[CH3:11])=[O:17])=[CH:18][CH:19]=1
Reactant: CC=C(OCC)OCC
Reactant: CCOC=C(C(C)=O)C(=O)NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCO[C@H]1C(C(=O)NCc2ccc(Cl)cc2)=C(C)OC(OCC)(OCC)[C@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
N-(4'-chlorobenzyl)-2-ethoxymethylene-3-oxobutanamide (1.4 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium (0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (4 g) was added dropwise. The mixture was stirred at room temperature for 3 days and evaporated to dryness. The residual gum was triturated with petroleum ether b.p. 60°-80° C. to give a solid which was recrystallised from a mixture of toluene and petroleum ether b.p. 60°-80° C. to give cis-N-(4'-chlorobenzyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.9 g) m.p. 97°-100° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[CH:7]=[N:8][C:9]=1[Cl:10].I[CH3:17]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]([CH3:17])[C:13](=[O:15])[CH3:14])[CH:7]=[N:8][C:9]=1[Cl:10]
Reactant: CC(=O)NCc1cnc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
NaH (41 mg, 1.0 mmol, Aldrich, 60% dispersion in mineral oil) was added portionwise to a solution of N-(5,6-dichloro-pyridin-3-ylmethyl)-acetamide (150 mg, 0.68 mmol, Example 155d) and iodomethane (0.063 mL, 1.0 mmol, Aldrich) in DMF (3.0 mL) with stirring at room temperature. The mixture was stirred for 30 min at room temperature, diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 80% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 233 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[O:17]=[C:18]([C@H:24]([CH3:40])[C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21].O>CCOCC.C1COCC1>[O:17]=[C:18]([C@H:24]([CH3:40])[C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:37])([Cl:38])[Cl:39])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[C@@H:20]([OH:21])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetate (0.865 mL) is added to a solution of lithium diisopropylamide (7.52 mmol) in 30 mL of ether at −78° C., and the mixture is stirred for 1 hour. A solution of bis(1,2:5,6-di-O-isopropylidene-α-L-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (8.34 mmol) in 90 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (4R,5S,6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonenal (2.57 g) in 15 mL of ether is added over 10 minutes and the reaction is continued for 2 hours before addition of 14 mL of 5 M water in THF. The mix is stirred for 1 hour then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (7% ethyl acetate/hexanes).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1.7 g, 7.4 mmol) and Et3N (1.12 g, 11.1 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1 g, 8.87 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was washed with brine. The organic layer was concentrated in vacuo to give crude tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperazine-1-carboxylate (2.1 g, 94%). This was used in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 4.38 (t, 2H, J=5.3 Hz), 3.49-3.44 (m, 4 h), 3.09 (s, 3H), 2.79 (t, 2H, J=5.1 Hz), 2.58 (t, 4 h, J=5.0 Hz), 1.49 (s, 9H). LCMS: No molecular ion observed for desired mass.
Reaction SMILES: [Na]C[C:3](=O)[CH2:4][C:5]([O:7]CC)=[O:6].[I-].[Na+].Cl[CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[CH3:19]C(C)=O>>[CH3:3][C:4]1([C:5]([OH:7])=[O:6])[CH2:19][C:14]([CH3:18])=[C:15]([CH3:16])[O:17]1
Reactant: CC(C)=O
Reactant: CC(=O)C(C)Cl
Reactant: CCOC(=O)CC(=O)C[Na]
Agent: [I-]
Agent: [Na+]
Product: CC1=C(C)OC(C)(C(=O)O)C1
Yield: 76 %

Procedure:
To a stirred and refluxing solution of ethyl sodioacetoacetate (153 g.), sodium iodide (2 g.) and dry acetone (500 ml.) was added 3-chloro-2-butanone (1.1 mol., 117 g.) and the refluxing and stirring continued for 11/2 hours. The precipitated sodium chloride was filtered off from the reaction mixture and the acetone was removed from the filtrate. To the residue, water was added and the oily intermediate extracted with benzene. The benzene solution was treated with p-toluenesulfonic acid (0.5g.) and heated under reflux collecting the water of cyclization-dehydration in a Dean-Stark trap. After the reaction was completed (2-4 hours) the benzene was removed and the residual ester was saponified as in example 18 to give 117 g. (yield 76%) of 2,4,5-trimethylfuroic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:19]([NH:18][C:17](=[N:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 66.6 %

Procedure:
To a solution of 3,5-dichloroaniline (11 mmol, 1.79 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 65 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 2.04 g of the title compound (67%); 1H-NMR (CDCl3): δ 7.12 (d, 2H), 7.22 (s, 1H), 7,35 (m, 3H), 7.45 (d, 2H), 9.4 ppm (br s,1H). EI SP/MS: 305 (M+), 307 (M+2), 309 (M+4).