Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15](=[O:60])[C@@H:16]([O:41]/[N:42]=[C:43](/[C:47]1[N:48]=[C:49]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:50][CH:51]=1)\[C:44]([OH:46])=O)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:40])[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:61]1([CH2:66][C@H:67]2[NH:70][C:69](=[O:71])[C@H:68]2[NH2:72])[CH:65]=[N:64][CH:63]=[N:62]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:61]1([CH2:66][C@@H:67]2[C@H:68]([NH:72][C:44](=[O:46])/[C:43](=[N:42]\[O:41][C@H:16]([C:15]([O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:60])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:40])[NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)/[C:47]3[N:48]=[C:49]([NH:52][C:53]([O:55][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:54])[S:50][CH:51]=3)[C:69](=[O:71])[NH:70]2)[CH:65]=[N:64][CH:63]=[N:62]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a solution of (S,Z)-2-(((1-(benzhydryloxy)-3-(4-(N-(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (Prepared according to WO2013110643, 72 mg, 0.085 mmol), (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (15.7 mg, 0.094 mmol) and HATU (42.2 mg, 0.111 mmol) in DMF (854 μL) was added DIPEA (44.8 μL, 0.256 mmol). After stirring at for 3 h it was diluted with EtOAc, washed with water, NaHCO3 (aq satd), brine, dried over Na2SO4 and concentrated in vacuo, affording the title compound (82 mg, 87%) as an olive film. LCMS: Rt=0.97 min, m/z=992.5 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[CH2:22])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>O1CCCC1.O.CO>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[CH2:22])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)OCC)sc(N2CCOCC2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (0.211 g, 0.453 mmol) in tetrahydrofuran (8.00 mL) was added 1.000 M of sodium hydroxide in water (10.0 mL) and methanol (4.00 mL). The resulting mixture was stirred at room temp over 3 hrs. The volatiles were removed under reduced pressure, and the resulting mixture was acidified with conc. HCl soln to pH ˜2, and extracted with EtOAc (×3). The combined org layer was dried and concentrated to provide a purple syrup. Purification of the crude mixture on HPLC (AA, reverse phase) provided 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (63 mg, 31.8% yield). LCMS: (AA) ES− 391, 393, 395; 1H NMR (400 MHz, MeOD) δ 7.54-7.46 (d, J=1.6 Hz, 1H), 7.45-7.35 (d, J=8.4 Hz, 1H), 7.34-7.24 (dd, J=8.4, 1.6 Hz, 1H), 5.88-5.68 (m, 2H), 5.16-5.05 (dd, J=17.1, 1.7 Hz, 1H), 5.00-4.92 (m, 1H), 3.82-3.71 (t, J=4.8 Hz, 4H), 3.51-3.40 (t, J=4.8 Hz, 4H), 3.05-2.95 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH2:10]OS(C)(=O)=O)[C:7]=2[CH:16]=1.[OH2:17].Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH2:10][N:19]3[CH2:24][CH2:23][C:22](=[O:17])[CH2:21][CH2:20]3)[C:7]=2[CH:16]=1
Reactant: O=C1CCCCN1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Reactant: O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(CN1CCC(=O)CC1)=C2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 12.11 g (50 mmol) of methanesulphonic acid (5-methoxybenzocyclobuten-1-ylmethyl) ester in 100 ml of dimethylformamide there are added first 8.45 g (55 mmol) of piperidone hydrochloride monohydrate and then 22.62 g (175 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 80° C. for 18 hours and, after cooling, is concentrated to dryness by evaporation under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic phase is separated off and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline at reduced temperature with sodium hydroxide solution and extracted with dichloromethane. The extracts are combined, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. A dark brown resin is obtained which is purified by chromatography on 350 g of silica gel (0.040-0.063 mm) with toluene/ethyl acetate (1:1). 1-[(5-methoxybenzocyclobuten-1-yl)methyl]piperidin-4-one is obtained in the form of a light-yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O>>[C:26]1([C:24]2[C:6]3[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=3[O:10][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:4]1([C:1]2[C:17]3[CH:18]=[C:13]([C:12]([F:20])([F:21])[F:11])[CH:14]=[CH:15][C:16]=3[O:19][CH:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCc1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: CCCc1ccc2occ(-c3ccccc3)c2c1
Product: FC(F)(F)c1ccc2occ(-c3ccccc3)c2c1

Procedure:
When 4-n-propylphenol or 4-trifluoromethylphenol is reacted with α-bromoacetophenone according to the procedure described in Example 14 and the resulting product is cyclized by heating with polyphosphoric acid at 80° as described therein, 3-phenyl-5-n-propylbenzofuran and 3-phenyl-5-trifluoromethylbenzofuran are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[CH3:34].C(C1C=CC(S([N:48]2C3C=C(C#N)C=CC=3NC3N=C(C(F)(F)F)C=CC=3[CH2:49]2)(=O)=O)=CC=1)(C)(C)C>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[C:33]([CH3:34])=[C:2]([C:49]#[N:48])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Product: Cc1c(C#N)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2

Procedure:
The title compound was prepared from 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 63) according to the procedure described for intermediate 54. Racemic mixture: LC/MS: m/e 501.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.63 (1H, d), 7.47 (1H, d), 7.19 (2H, d), 7.13 (1H, d), 7.00 (2H, d), 5.20 (1H, d), 4.45 (1H, d), 2.65 (3H, s), 1.25 (9H, s). The racemic mixture was separated into individual enantiomers via chromatography on a Chiracel OD column eluting with 15% EtOH in hexanes at 8.0 mL/min. The faster eluting enantiomer E1 has a retention time of 9.77 min. The slower eluting enantiomer E2 has a retention time of 12.04 min.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.N1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(O)C>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(C(=O)n2cc(F)c(=O)[nH]c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 49.2 %

Procedure:
1.3 g (0.01 mole) of 5-fluorouracil was suspended in a mixed solution of 40 ml. of dioxane and 2 ml. of pyridine. 1.7 g (0.01 mole) of p-methoxybenzoyl chloride in 5 ml. of dioxane was added to the suspension and stirred at 80°C. for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in ethanol and filtered. After cooling to 0°C., the resulting crystals were filtered and dried to give 1.30 g (49.2% yield) of 5-fluoro-1-(p-methoxybenzoyl)uracil. The product was recrystallized from dioxane-ethanol and white needles melting at 200°-201°C. were obtained. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(CC2CCCN2)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCCC1Cc1ccccc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (12.5 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1398.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1.C[OH:28].Cl>CCOC(C)=O>[OH2:28].[ClH:1].[N:18]1([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3=[CH:9][C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:11][C:3]=23)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CO
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCc3ccccc32)c2nc(-c3ccccc3)cc-2[nH]1
Product: O
Temperature: 180 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (350 mg, 1.44 mmol) and indoline (Aldrich Chemical Company) (350 mg, 2.94 mmol). The flask was purged with N2 and the mixture was heated to 180° C. for 1 h. The reaction was allowed to cool to room temperature and the crude material was purified by silica gel chromatography with 33% EtOAc/hexanes to give 250 mg (53% yield) of an off white solid. The free base (221 mg, 0.677 mmol) was dissolved in hot EtOAc (15 mL)and MeOH (2 mL) and anhydrous ethereal HCl (0.677 mL, of a 1.0 M soln, 0.677 mmol) was added dropwise. The mixture was stirred for 2 h and allowed to cool to room temperature. The resulting solid was filtered and dried under high vacuum to give 239 mg (97% yield) of the title compound as a light yellow solid. Mp: >300° C. 1H NMR (DMSO-d6; 400 MHz): d 2.7 (s, 3), 4.87 (t, 2, J=8.2), 7.0 (s, 1), 7.17 (t, 1, J=7.5), 7.32 (t, 1, J=7.6), 7.58 (m, 3), 8.0 (d, 2, J=6.9), 8.53 (d, 1, J=3.3), 11.7 (br, 1), 14.55 (br, 1). MS m/z: 327.0 (M+1); 325 (M−1). Anal. Calcd for C21H18N4.1.0HCl.1.25H2O: C, 6.5.45; H, 5.62; N, 14.54. Found: C, 65.62;, H, 5.62; N, 14.49.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A20) (3.0 g, 9.77 mmol) and isobutylamine (3.57 g, 48.8 mmol) in DMSO (20 mL) at 55° C. according to the general procedure C. Obtained as a brown solid (2.26 g, 67%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:13][C:11](=[O:12])[N:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:8]1=[O:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[O:9]=[C:8]1[N:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:3](=[O:4])[CH3:2])[C:11](=[O:12])[CH2:13][N:7]1[CH3:6]
Reactant: COc1ccccc1NCN1C(=O)CN(C)C1=O
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1N(CN1C(=O)CN(C)C1=O)C(C)=O
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a solution of 7 g of the 1-methyl-3-(2-methoxyphenylaminomethyl)hydantoin and 2.8 g of pyridine in 40 ml of toluene at -10° C. The suspension was stirred on an ice-bath for 1.5 hrs. The resulting precipitate was filtered and thoroughly washed with 5% hydrochloric acid, water, and recrystallized from chloroformether to give 6.0 g of N-(2,4-dioxo-1-methylimidazolidin-3-ylmethyl)-N-(2-methoxyphenyl)acetamide, mp 169°-172° C; M+ = 325.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: COc1ccccc1N=C=O
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2OC)n1

Procedure:
Following a procedure similar to that described in preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of o-methoxyphenyl isocyanate and 40 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][O:17][CH:18]([O:20][CH2:21][CH2:22]I)[CH3:19]>O1CCCC1>[C:3]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH2:16][O:17][CH:18]([O:20][CH2:21][CH2:22][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH3:19])([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(OCCI)OCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOC(C)OCCC(C(=O)OCC)C(=O)OCC)C(=O)OCC
Yield: 61.6 %

Procedure:
5.28 g (0.11 mol) of sodium hydride was added to 50 ml of dry tetrahydrofuran, and to this solution was added dropwise a mixed solution of 17.6 g (0.11 mol) of diethyl malonate and 10.0 g (0.027 mol) of bis(2-iodoethoxy)ethane, followed by 2-hour reflux under heating. After the reaction, the most part of tetrahydrofuran was distilled off and the residue was added with 10 ml of water, neutralized by adding 1N hydrochloric acid and extracted three times with 50 ml of ether. After drying the extract, ether was distilled off and the oily product was passed through a silica gel packed column and eluted with petroleum ether-ether (4:1) to obtain 7.23 g of bis(3,3-dicarboethoxypropoxy)ethane, (EtO2C)2CHCH2CH2OCH2CH2 -OCH2CH2CH(CO2Et)2 (yield: 60%). The property analyses of this compound showed the following results.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([OH:50])[C@H:28]([O:29][Si](C)(C)C)[C@@H:27]([O:34][Si](C)(C)C)[C@H:26]([O:39][Si](C)(C)C)[C@@H:25]([CH2:44][O:45][Si](C)(C)C)[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[C:18]([C@@:23]3([O:50][CH3:51])[C@H:28]([OH:29])[C@@H:27]([OH:34])[C@H:26]([OH:39])[C@@H:25]([CH2:44][OH:45])[O:24]3)[CH:19]=[CH:20][C:21]=2[Cl:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: C[Si](C)(C)OC[C@H]1O[C@@](O)(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol 25d in anhydrous tetrahydrofuran was added a solution of methylsulfonic acid (0.2 mL, 2.82 mmol) in methanol (20 mL) at −78° C. The mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (50 mL×4). The combined organic layers were washed with water (60 mL×2) and saturated aqueous sodium chloride (60 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/n-hexane mixture ((v/v)=1/20, 500 mL) to give the title compound 25e as a white solid (1.28 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 545.3[M+HCOO]−.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[H-].[Na+].[CH2:15](OS(OCC)(=O)=O)[CH3:16].O>CS(C)=O>[CH2:15]([O:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:16]
Reactant: CCOS(=O)(=O)OCC
Reactant: OCC1Cc2ccccc2CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC[C@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 500 mg (3.06 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 10 mL of DMSO was added 122 mg (3.06 mmol) of NaH (60% in oil) and the mixture was stirred for 45 minutes at room temperature. Then 0.403 mL (3.06 mmol) of diethylsulfate was added via syringe. Foaming occurred and subsided in approximately 15 minutes. The reaction mixture was then stirred at room temperature overnight and poured into water. The product was extracted into ethyl acetate and dried and evaporated to an oil. This was chromatographed on silica gel to give the desired product as an oil, 190 mg. 1H-NMR (CDCl3) δ 1.22 (3H, t, J=7), 2.29 (1H, broad s), 2.55-2.70 (2H, m), 3.09-3.18 (1H, m), 3.41 (1H, t, J=7), 3.50-3.59 (3H, m), 4.06 (2H, ABq, J=5, 21), 7.00-7.13 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:16]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[CH3:14])=[CH:23][CH:22]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: CC(=O)Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (138 mg, 0.72 mmole) and 4-aminoacetanilide (1.50 g, 10.0 mmole) is stirred under N2 at 200 °C. for 1 h. The resulting product is chromatographed over alumina (8-10% MeOH/CH2Cl2) to give 7-amino-4-(4-acetamidoanilino)pyrido[4,3-d]pyrimidine (110 mg, 52%) as a pale yellow solid. 1H NMR (DMSO) δ 9.94, 9.79 (1H, 1H, 2 brs), 9.31 (1H, s), 8.34 (1H, s), 7.69 (2H, d, J=8.9 Hz), 7.57 (2H, d, J=8.9 Hz), 6.57 (2H, brs), 6.43 (1H, s), 2.05 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1.[CH3:12][S-:13].[Na+]>CO>[CH3:9][S:8][C:6]1[NH:5][C:4]([S:13][CH3:12])([NH:10][NH2:11])[CH:3]=[CH:2][N:7]=1
Reactant: CSc1nc(Cl)cc(NN)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSC1=NC=CC(NN)(SC)N1
Temperature: 20 °C
Yield: 65.1 %

Procedure:
A mixture of the known compound 6-chloro-4-hydrazinyl-2-methylthiopyrimidine (15 g, 0.079 mole) and 21 g (0.1 mole) of sodium methyl mercaptide in 250 ml of methanol was heated at reflux for about 16 hours, and was then allowed to cool to about 20° C. The solid precipitate was separated by filtration, washed with methanol and water and dried. The filtrate was evaporated to provide a solid residue. This residue was then washed thoroughly with water and combined with the precipitate. The solids were dissolved in 500 ml of acetic acid, and the solution was treated with decolorizing charcoal, and filtered. The filtrate was cooled and treated with ammonium hydroxide until it was slightly basic. The precipitate was collected by filtration, providing 10.5 g (65%) of 2,6-bis(methylthio)-6-hydrazinylpyrimidine, m.p. 120°-125° C.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](C#C)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O=C(C1C=CC([Br:30])=CC=1)CCC(C)C.C[Al](C)C>CCCCCC>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(C(C)(C)CCC(C)C)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)CCC(C)(C)c1ccc(Br)cc1

Procedure:
Reaction Scheme 6 discloses specific synthetic steps leading to 4-(1,1,4-trimethylpentyl)phenylethyne (Compound 34). In this synthetic route 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31, obtained for example as shown in Reaction Scheme 5) is reacted under a protective nitrogen atmosphere with trimethylaluminum in hexane to yield 4-(1,1,4-trimethyl-pentyl)bromobenzene (Compound 35). The bromobenzene derivative 35 is converted through the corresponding trimethylsilylethyne derivative 36 into the target intermediate 34 by treatment with trimethylsilyl ethyne and subsequently with KOH in isopropanol, as described above. ##STR10##
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([CH3:14])=[N:8][C:7]=2[N:6]([CH3:15])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:15])[C:7]=4[N:8]=[C:9]3[CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: CCn1c(=O)c2[nH]c(C)nc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(C)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
To a solution of l-ethyl-3,8-dimethylxanthine (170 mg), a synthetic process for which is described in Journal of American Chemical Society , 75, 114 (1953), in DMF (8 ml) were added potassium carbonate (169 mg) and 4-(4-chlorobenzoyl)benzyl bromide (278 mg) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate, and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized (ethyl acetate-hexane) to provide the title compound as colorless powder (87 mg, 24%).