Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1CC#N.[OH-:12].[Na+].Cl.[CH2:15]([OH:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:16][C:15]([OH:12])=[O:17]
Reactant: CCO
Reactant: N#CCc1cc(Cl)ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1cc(Cl)ccc1Cl
Temperature: 140 °C

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (5.4 g, 22.5 mmol) in 16 mL of ethanol and potassium cyanide (1.63 g, 25 mmol) in 4 mL of water was heated at 80° C. overnight, then cooled, and the solids were filtered and washed with ethanol to give 3.5 g of 2,5-dichlorophenylacetonitrile as a white powder melting at 89-91° C. The nitrile was suspended in 20 red, of ethanol, and 20 mL of a 25% aqueous NaOH solution was added. The mixture was heated in a CEM Explore™ microwave reactor at 140° C. for 30 minutes, then cooled, poured into ice water and acidified to pH 1 with concentrated HCl to give a precipitate. The precipitate was filtered, washed with water and dried in a vacuum oven at 90° C. for 5 h to give the title compound as a white powder.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[CH2:7]OS(=O)(=O)[O:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS(O)(=O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C@H:3]([OH:4])[CH2:7][NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:15][CH:16]=1
Reactant: O=S1(=O)OC[C@H](CCl)O1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1COCCN1c1ccc(NC[C@@H](O)CCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
Under an atmosphere of nitrogen to a solution of a 14.22 g of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (MW=156.59; 1.37 eq.) in 190 mL of methylenechloride were added 12.68 g of 4-(4-amino-phenyl)-morpholin-3-one (APMO) (MW=192.22; 1 eq.) and 9.2 g (MW=101.12; 1.37 eq.) of triethylamine. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was concentrated in vacuo and the concentrate was dissolved in 400 mL of acetonitrile. 38 g of methane sulfonic acid (MW=96.11; 6.0 eq.). and 7.9 g of water (MW=18.02; 9.0 eq.) were added and the solution were stirred at ambient temperature. After stirring for 5 h, the reaction mixture was neutralized by addition of 50 g of sodium hydrogencarbonate (MW=84.01; 9.0 eq.). The resulting suspension was filtered and the cake washed with 200 mL of acetonitrile. The combined acetonitrile layers were concentrated in vacuo. To the concentrate were added 260 mL of 2-propanol and the mixture was stirred for 1 h at ambient temperature. The resulting slurry was cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 50 mL of 2-propanol. After drying in vacuo at 30° C., 11.75 g of the crystalline title compound (MW=284.75) were isolated. Yield=62.6%.
Reaction SMILES: [NH2:1][C:2]1[C:16]([C:17]([OH:19])=O)=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][C:51]=1[NH2:56]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:16]([C:17]([NH:56][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][C:50]=2[CH3:49])=[O:19])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1ccncc1N
Reactant: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1ccncc1NC(=O)c1c(N)nn2ccc(OCCN(C)C)nc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a suspension of 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.377 mmol) in NMP (667 μL) was added Et3N (46.54 mg, 64.1 μL, 0.4599 mmol) in one portion. The mixture was stirred for 10 minutes before adding TBTU (Boron Tetrafluoride Ion) (136.3 mg, 0.4245 mmol), portionwise, over 5 minutes. The mixture was allowed to stir at room temperature for 20 mins. 4-Methylpyridin-3-amine (40.77 mg, 0.377 mmol) was added and the mixture was heated to 100° C. for 4 hours. The mixture was filtered through a silica gel pad and eluted with DCM initially followed by 20/80 MeOH/DCM. The residue was further purified by preparative HPLC to provide compound I-C-3 (42% yield). LC-MS (M+H)+=356.2; 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.38 (brs, 1H), 9.20 (brs, 1H), 8.82 (d, 1H), 8.50-8.43 (m, 1H), 7.66-7.6 (m, 1H), 6.62 (d, 1H), 6.50 (brs, 2H), 4.81-4.78 (m, 2H), 3.63-3.60 (m, 2H), 2.95 (s, 6H), 2.55 (s, 3H);
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[CH:29]1[CH:30]=CC2N(O)N=NC=2[CH:34]=1.CCN=C=NCCCN(C)C.C(CN1C2C(=CC=CC=2)CC(NC(C2NC3SC(Cl)=CC=3C=2)=O)C1=O)(O)=O>CN(C=O)C>[CH3:34][C:29]1([CH3:30])[O:26][CH:23]([CH2:22][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH:12]([NH:11][C:9]([C:7]3[NH:6][C:5]4[S:28][C:2]([Cl:1])=[CH:3][C:4]=4[CH:8]=3)=[O:10])[C:13]2=[O:27])[CH2:24][O:25]1
Reactant: On1nnc2ccccc21
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9; 243 mg, 1.20 mmol), HOBT (178 mg, 1.32 mmol), anhydrous DMF (10 mL) and finally EDCI (252 mg, 1.32 mmol) were added to 3-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (Method 2, 330 mg, 1.20 mmol) and the reaction was stirred for 18 h. The reaction was evaporated and the residue was dissolved in EtOAc (100 mL) and washed with 1M aqueous HCl (50 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc:hexanes 1:2) to afford the title compound (382 mg, 69%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCCCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Yield: 7.7 %

Procedure:
A solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (150.mg, 0.32 mmol), piperidine (0.03 mL, 0.32 mmol) and 2-methyl-2-(1-piperidyl)propanal (74.08 mg, 0.48 mmol) in ethanol (8 mL) was heated in a sealed tube at 90° C. for 16 hrs. The solution was cooled and concentrated. The residue was dissolved in ethyl acetate and washed with 5% citric acid and brine and then dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 grams column at 0% to 6% MeOH/ethyl acetate) to obtain 15 mg (8%) of the title compound. MS (pos. ion) m/z: 609 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[NH:14][C@@H:15]([CH3:27])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C([O-])=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[N+:1]([C:4]1[CH:43]=[CH:42][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[NH:14][C@@H:15]([CH3:27])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1

Procedure:
To a solution of the compound (1.59 g), which had been obtained in (1), in anhydrous dichloromethane (6 ml), trifluoroacetic acid (3 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[N+:28]([O-:30])=[O:29])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(N2CCN(Cc3ccccc3)CC2CC(=O)O)c1
Temperature: 90 °C

Procedure:
To a solution of Example 12C (0.907 g, 3.65 mmol) in acetonitrile (11.69 mL) was added 2-fluoro-4-methoxy-1-nitrobenzene (0.50 g, 2.92 mmol) and potassium carbonate (2.019 g, 14.61 mmol) in water (2.92 mL) followed by 18-crown-6 (0.039 g, 0.146 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 24 hours. The solvent was evaporated and water was added followed by dichloromethane. The water phase was washed three times with dichloromethane to remove starting material and then acidified with 1 N HCl until pH=1. The acid product was extracted three times with dichloromethane, dried quickly with sodium sulfate and concentrated to give the title compound. MS (ESI) m/z 386.1 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:22]1([CH3:32])[CH2:27]C[CH:25]([CH:28](C)[CH3:29])[CH:24](O)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH:23]([CH:22]([CH3:32])[CH3:27])[CH2:24][CH2:25][CH:28]([CH3:29])[CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CCC(C(C)C)C(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)C1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 62.5 g of menthol and 4 g of Na2CO3 were reacted with one another at 185-200° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 6 h, the reaction mixture was cooled and distilled under reduced pressure, giving 44 g (57%) of menthyl 2-cyano-3,3-diphenylacrylate [λmax=300 nm, E11=351].
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cccnc2)c1
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
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.6 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-3-yl-phenylamine (38.7 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 71.6 mg of product in 84% yield: LCMS (ESI) m/z 373 (MH+).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[N:6]([CH2:16][CH:17]=C)[S:5]1(=[O:20])=[O:19])[CH3:3].[H-].[Na+].CC(N1CC2C=C(SC)C=CC=2NS1(=O)=O)C.[H][H].BrCC[Cl:45]>CN(C=O)C.CCCCCC>[Cl:45][CH2:17][CH2:16][N:6]1[C:7]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:8]=2[CH2:9][N:4]([CH:2]([CH3:3])[CH3:1])[S:5]1(=[O:20])=[O:19]
Reactant: [H][H]
Reactant: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O
Reactant: ClCCBr
Agent: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250 ml 3 necked flask equipped thermometer, pressure equalised dropping funnel, nitrogen bubbler and magnetic stirrer bar was added 60% sodium hydride (1.77 g, 1.062 g, 0.04425 mol,) hexane washed, to dry DMF (75 ml). To this stirred suspension was added dropwise a solution of 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10.0 g, 0.0368 mol) in dry DMF (75 ml) (slight exotherm). The suspension was stirred under nitrogen for 2 hr until hydrogen evolution ceased. 1-Bromo-2-chloroethane (6.33 g, 3.77 ml, 0.04425 mol) was added dropwise and the reaction mixture allowed to stir at room temperature under nitrogen overnight. The reaction mixture was poured onto ice-water (800 ml) with stirring for 1 hr, filtered and washed with water (200 ml) to leave a white solid which was dried in vacuo at 50° C. to give a solid. Mp 74-75° C.
Reaction SMILES: N1CC[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]([NH2:20])=[NH:19])[N:12]=1.[C:21](O)(=O)[CH3:22]>C(#N)C.CO>[CH3:10][C:11]1[C:16]([CH:21]=[CH2:22])=[C:15]([CH3:17])[N:14]=[C:13]([C:18]2[N:20]=[CH:4][CH:3]=[CH:2][N:19]=2)[N:12]=1
Reactant: Cc1cc(C)nc(C(=N)N)n1
Reactant: CC(=O)O
Reactant: C1CCNCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: C=Cc1c(C)nc(-c2ncccn2)nc1C
Yield: 60.86 %

Procedure:
In a manner similar to that described in Example 13, a solution of α-vinyl-β-piperidylacrolein is prepared from 12.94 g (0.104 mole) of 5-formyl-α-pyrone and 8.84 g or 10.26 ml (0.104 mole) of piperidine in 84 ml of acetonitrile. In a separate reaction vessel, 18.31 g (0.104 mole) of sodium methylate in 70 ml of methanol are added to 19.46 g (0.104 mole) of 4,6-dimethylpyrimidylamidine hydrochloride in order to set free the corresponding base. The acetonitrile solution of α-vinyl-β-piperidylacrolein is then mixed with the methanolic suspension of the 4,6-dimethyl-2-pyrimidine-amidine base and the reaction mixture is refluxed for 3 hours, while adding dropwise 6.24 g, i.e. 5.88 ml (0.104 mole), of glacial acetic acid. The suspension is filtered with suction and the filtrate is washed with 20 ml of methanol. The filtrate is evaporated to dryness and the residue is chromatographed over a column of silica gel (1000 g of SiO2 ) with chloroform/methanol in the volume ratio 19:1 as eluant. The product (14.1 g=63.95% of theory) is stirred in diethyl ether, filtered with suction and dried at 80° C./100 bar, affording 13.42 g (60.86% of theory) of 4,6-dimethyl-2-pyrimidyl-5-vinylpyrimidine with a melting point of 230°-232° C. The product is readily sublimable at 160° C./2×10-3 bar. The melting point is not raised thereby.
Reaction SMILES: Br[C:2]1[C:3]([NH2:23])=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]3[CH2:12][C:13]4([CH2:18][CH2:19][C:7]3([CH2:20][CH3:21])[C:6]=2[CH:22]=1)[O:17][CH2:16][CH2:15][O:14]4.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CB1OB(C)OB(C)O1>COCCOC.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([C:7]12[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:8]1[CH2:9][CH2:10][CH2:11][C:5]1[CH:4]=[C:3]([NH2:23])[C:2]([CH3:24])=[CH:22][C:6]=12)[CH3:21]
Reactant: CCC12CCC3(CC1CCCc1cc(N)c(Br)cc12)OCCO3
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCC12CCC3(CC1CCCc1cc(N)c(C)cc12)OCCO3
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of rac-(4aR,11bS)-10-bromo-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (23, R2=Ethyl) (0.255 g, 0.670 mmol) in DME (6 mL) and water (2 mL) was degassed by bubbling nitrogen through the mixture for about 15 min. Cesium carbonate (0.655 g, 2.011 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.168 g, 1.341 mmol) and PdCl2(PPh3)2 (0.024 g, 0.034 mmol) were added and the mixture was heated to about 90° C. for about 22 h. The mixture was cooled to rt, diluted with EtOAc (25 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-15% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (24, R2=Ethyl) (0.112 g, 53%); LC/MS, method 3, Rt=2.53 min, MS m/z 316 (M+H)+. 1H NMR (400 MHz, DMSO) δ 6.72 (s, 1H), 6.35 (s, 1H), 4.61 (s, 2H), 3.88-3.70 (m, 4H), 2.79-2.72 (m, 1H), 2.54-2.47 (m, 1H), 2.33-2.27 (m, 1H), 2.13-2.04 (m, 1H), 2.00 (s, 3H), 1.97-1.88 (m, 2H), 1.72-1.57 (m, 3H), 1.53-1.46 (m, 1H), 1.41-1.14 (m, 5H), 0.59 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+].C(OCCOCCO)C>O>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)=[O:21]
Reactant: CCN(CCCl)c1ccc(C=O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCCOCCO
Product: CCN(CCOc1ccc(C=O)cc1)c1ccc(C=O)cc1

Procedure:
A mixture of 4-[[2-Chloroethyl)ethylamino]benzaldehyde 10.6 g (0.05 m), p-hydroxybenzaldehyde (6.1 g, 0.05 m), 50% NaOH (4.4 g), water (50 mL), and 2-(2-ethoxyethoxy)ethanol was heated at reflux for 6 hours and then allowed to cool. A semi-solid product was obtained which was washed with water by decantation and recrystallized from methanol. After being collected by filtration, washed with methanol, and dried in air the product weighed 6.5 g and the structure was confirmed by mass spectral analysis to be as follows: ##STR14##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([O:20][Si](C(C)(C)C)(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O[Si](C)(C)C(C)(C)C)CC1NC(=O)OCc1ccccc1
Agent: F
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate (1.45 g, 3.69 mmol) in THF (35 mL) under N2 was added HF•pyridine (1.0 mL, 38 mmol). The reaction mixture was stirred for 5 h. After this time, additional HF•pyridine (1.0 mL, 38 mmol) was added and stirring was continued for 19 h. The reaction mixture was then cooled to 0° C. and diluted with Et2O (150 mL). The mixture was then carefully quenched with saturated aqueous NaHCO3 until gas evolution ceased. At this time, the organic layer was separated and the remaining aqueous layer was extracted with Et2O (300 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 20%-50% EtOAc/hexanes afforded the title compound (0.960 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.11-4.83 (m, 3H), 4.21 (q, J=7.2 Hz, 2H), 3.37-3.25 (m, 2H), 1.73-1.68 (m, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.14-1.06 (m, 1H); ESI MS m/z 280 [M+H]+.
Reaction SMILES: [C:1](=[O:7])([O:3][CH:4]([CH3:6])[CH3:5])[NH2:2].[C:8](Cl)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].CC(C)([O-])C.[Li+].Cl>C(OCC)C.O1CCCC1>[C:8]([NH:2][C:1](=[O:7])[O:3][CH:4]([CH3:6])[CH3:5])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C/C=C/C(=O)NC(=O)OC(C)C
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Isopropyl carbamate (30 g, 291 mmol, available from TCI) was charged to a 3 L Lara vessel and dry tetrahydrofuran (THF) (150 ml) added. (2E)-2-Butenoyl chloride (31.2 ml, 326 mmol, available from Aldrich) was added under nitrogen and the jacket cooled to −30° C. When the solution temperature reached −17° C. Lithium tert-butoxide (1M, 655 mL, 655 mmol) was added by peristaltic pump over 2 h, keeping the reaction temperature between −10° C. and −18° C. Once the addition was complete the mixture was stirred for 30 min and brought to 0° C. Diethyl ether (450 ml) and hydrochloric acid (1M, 375 mL) were added and the mixture brought to 20° C. with vigourous stirring. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. Brine (375 mL) was added and the mixture stirred vigourously. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. The organic layer was dried (MgSO4), filtered and evaporated to a brown oil (60 g). The was applied to a silica column (40+M Biotage) and eluted with DCM/ethyl acetate (1:1 to 0:1, 10 CV). The product containing fractions were evaporated to dryness and loaded on to a Redisep Isco silica column (1500 g) and eluted with a gradient ethyl acetate in cyclohexane (0-40%). The clean, product containing fractions were evaporated to an off-white solid (15.41 g). LCMS (Method C): Rt=0.68, MH+=172