Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C[N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:10]2[CH2:9]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:9]1[CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]2[CH2:25][CH2:26][N:8]1[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Ethyl chloroformate (19.53 g) was added dropwisely to a solution of 9.52 g of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine in 48 ml of benzene at refluxed temperature and the mixture was refluxed for 5 hrs. Ice water was added to the reaction mixture and made alkaline with sodium bicarbonate. The mixture was extracted with benzene and the benzene layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate as an eluent (1:2) to give 8.70 g of pale yellow crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give pale yellow prisms, mp 108.5°-109.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]([O:15]CC)=O)[C:11](=O)[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][NH2:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:11](=[N:31][N:30]([CH3:29])[C:13]=3[OH:15])[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CNN
Reactant: CCOC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C)c(O)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 57 using ethyl 2-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dioxopyrrolidine-3-carboxylate (Step 73.2) and methyl hydrazine at reflux for 32 hr. tR: 0.68 min (LC-MS 2); ESI-MS: 385 [M+H]+, ESI-MS: 383 [M−H]− (LC-MS 2); Rf=0.23 (CH2Cl2/7.5% MeOH/1% AcOH); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (s, 3H) 3.34 (s, 3H) 3.44 (m, 3H) 5.62 (s, 1H) 7.09 (d, J=8.6 Hz, 2H) 7.17-7.34 (m, 3H) 7.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[N+:13]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#N)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C#N)cc1N

Procedure:
2-t-Butyl-5-cyano-l-nitrobenzene [prepared as described in step (i) above] was reduced in a similar manner to that described in Preparation 5 to give the title compound as crystals, melting at 94.5-95° C. (from hexane-ethyl acetate).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:19][C:18](=[O:24])[N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[CH3:26])[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[CH3:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(C)c1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-dimethylphenyl)boronic acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale -yellow oil (yield 177 mg, 56%).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([OH:23])([CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[OH:23][C:15]1([CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH2:16][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:11]([OH:13])=[O:12])[CH2:14]1
Reactant: CC(=O)SCCC(=O)N1CC(O)(Cc2cccs2)C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CC(O)(Cc2cccs2)CN1C(=O)CCS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-L-proline.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([N:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][N:7]3[NH:20][C:21]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:6]3[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:9]([N:10]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][N:7]3[N:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C1=C(c2ccc(F)cc2)NN2C=C(N(CCC(C)C)S(C)(=O)=O)C(C3CC3)=CC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCC(C)C)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of Example 17K in dimethyl sulfoxide (8 mL) was treated with potassium carbonate (237 mg, 1.71 mmol) and iodobenzene diacetate (552 mg, 1.71 mmol) followed by stirring for 1 hour. The mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford a brown oil. Purification by chromatography on a 100 g silica gel cartridge, eluting with 15-80% ethyl acetate in hexanes, afforded the title compound as a rigid foam (166 mg, 23% over two steps). 1H NMR (500 MHz, CDCl3) δ ppm 8.48 (s, 1H), 7.75 (m, 2H), 7.67 (s, 1H), 7.15 (m, 2H), 3.82 (s, 3H), 3.68 (m, 1H), 3.64 (m, 1H), 3.07 (s, 3H), 2.29 (m, 1H), 1.62 (m, 1H), 1.51 (m, 1H), 1.23 (m, 2H), 1.07 (m, 1H), 0.94 (m, 6H), 0.82 (m, 1H); MS (ESI+) m/z 474 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:11].[H][H]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:11].[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)cc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(O)cc1F

Procedure:
2-Fluoro-4-hydroxybenzonitrile (10 g, Allied Signal) was added to a 500 mL Parr flask, followed by palladium hydroxide (5 g). Anhydrous ethanol (200 mL) was then added under nitrogen atmosphere, followed by aq. concentrated hydrochloric acid (7.55 mL). The mixture was shaken under 50 psi of hydrogen for 1.5 h, then filtered through nylon. The filtrate was concentrated, washed with ethyl acetate, then dried in vacuo to yield the crude title compound (9.8 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([F:23])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([F:23])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: COC(=O)c1cc2c(cc1F)CC[C@H]2N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(cc1F)CC[C@H]2NC(=O)c1ccccc1Cl
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Triethylamine (2.5 eq.) was added to a solution of (R)-methyl 3-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-11) (0.773 mmol, 1 eq.) in methylene chloride (6 ml) at 0° C. and the mixture was stirred for 10 min. 2-Chlorobenzoyl chloride (1.2 eq.) was added dropwise to the reaction mixture at the same temperature and the mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with methylene chloride (50 ml) and was then washed with NH4Cl solution (20 ml) and sat. NaCl solution (20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography (silica gel, ethyl acetate/cyclohexane 2:1) to yield the desired product (B-15). Yield: 97%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11].C(N(CC)CC)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>ClCCl>[CH2:34]([S:37]([O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11])(=[O:39])=[O:38])[CH2:35][CH3:36]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)n1ncc(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Oc1c(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)cnn1C(C)C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
0.85 g (2.60 mmol) of 6-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl carbonyl)-2-methyl-4-phenyl-1,2,4-triazine-3,5 (2H, 4H)-dione was dissolved in 20 ml of dichloromethane. To the solution, 0.27 g (2.60 mmol) of triethylamine and 0.37 g (2.60 mmol) of 1-propane sulfonyl chloride were added at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residues were purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.71 g of the target compound (yield 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:59][C:56]1[S:57][C:58]2[C:50]([CH:45]3[CH2:46][O:47][CH2:48][CH2:49][O:44]3)=[CH:51][CH:52]=[C:53]([O:60][CH3:61])[C:54]=2[N:55]=1)=[O:7]
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of 789 mg (3.91 mmol) 2-bromo-isonicotinic acid in 50 ml THF were added 1.71 g (4.51 mmol) HATU and 1.29 ml (7.51 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 800 mg (3.00 mmol) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine was then added and stirring continued at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (acetone) followed by trituration in ether afforded 1.35 g (99%) (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide as a light yelllow solid. [α]D20=+12.9° (c=0.76, CHCl3), ES-MS m/e (%):452 (M{81Br}+H+, 95), 450 (M{79Br}+H+, 100).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:23](=[CH:24][CH:25]=2)[O:22][C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][C:14]3=[O:26])=[CH:7][CH:6]=1.[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39]([N:19]4[CH2:18][CH2:17][C:16]5([CH2:15][C:14](=[O:26])[C:13]6[C:23](=[CH:24][CH:25]=[C:11]([C:8]7[CH:9]=[N:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=7)[CH:12]=6)[O:22]5)[CH2:21][CH2:20]4)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:28][CH2:29]1
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Reactant: COc1ccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5nnn[nH]5)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-[6-(Methyloxy)pyridin-3-yl]spiro[chroman-2,4′-piperidin]-4-one dihydrochloride (238 mg), 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (135 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 ml) were suspended in DMF (3 ml), and stirred at 50° C. for 16 hours. 1N hydrochloric acid and water were added to the reaction liquid, the formed solid was taken out through filtration, and the resulting solid was recrystallized from methanol to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.43 (1.0H, d, J=2.7 Hz), 7.98 (1.0H, dd, J=8.7, 2.7 Hz), 7.93-7.88 (2.0H, m), 7.87-7.83 (2.0H, m), 7.65 (1.0H, d, J=3.2 Hz), 7.21 (1.0H, d, J=8.3 Hz), 7.12 (1.0H, d, J=3.2 Hz), 6.88 (1.0H, d, J=8.3 Hz), 4.50-3.97 (1.0H, m), 3.88 (3.0H, s), 3.80-3.17 (4.0H, m), 2.94 (2.0H, s), 2.17-1.91 (2.0H, br m), 1.89-1.77 (2.0H, m), 1.16-1.09 (2.0H, m), 1.04-0.99 (2.0H, m). MS [M+H]+=576.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)(Cl)Cl>[C:3]1([CH3:2])[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:20]([Cl:19])[S:23][N:8]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 5 °C
Yield: 44 %

Procedure:
To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0 mmol) in CHCl3 (100 ml) is added triethyl amine (15.12 g, 20.9 ml, 150.0 mmol) and cooled to 5° C. in an ice-water bath. To the mixture is slowly added perchloromethyl mercaptan (95%, 6.16 g, 31.5 mmol) in CHCl3(10 ml) over 1 hour. The yellow solution is allowed to warm up to room temperature. After 2 hours the mixture is washed with water (100 ml×2) and brine (100 ml). The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure to yield a brown oil. The oil is purified on a bed of silica gel, eluting with 1:1 CHCl3:hexanes to yield 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole as a yellow solid (2.78 g, 44%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])(C)C[C:4]([CH3:10])=[CH:3]1.[CH:11]12C[CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2>ClCCl>[CH3:8][CH2:6][CH2:9][C:2](=[O:1])[CH2:3][CH2:4][CH2:10][CH2:15][CH2:16][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=CC2CCC1C2
Solvent: ClCCl
Product: CCCCCCCCCC(=O)CCC

Procedure:
To a Pyrex photoreactor equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 103.6 g. (0.75 mol.) of isophorone and 400 g. (4.25 mol) of freshly distilled bicyclo [2.2.1] hept-2-ene. The vessel was filled to its internal volume of 1200 ml. with dichloromethane. The solution was bubbled with nitrogen for 1 hour and irradiated through a Pyrex filter for 18.5 hours with an Hanovia 450 watt medium pressure mercury arc. After the lamp was turned off, the solution was concentrated in vacuo to obtain an oil which was distilled through a 90 cm. Vigreux-column to yield 143.6 g. (0.62 mol., 82%) of the desired product having b.p. 90°-94° C./0.5 mm.Hg. Glpc showed the product to be a 1:1 mixture of two main isomers (180 cm. × 0.3 cm. 1% OV-225 on Chrom G, 150° C. initially for 3 min. and then programmed 10° C./min. to 250° C.) IR: 1692 cm-1NMR: (CCl4) singlets at 1.35δ, 1.10δ, 1.00δ, 0.92δ, 0.87δ with the singlet at 1.00δ having an integral area of 6H while the others integrated to 3H. The rest of the NMR spectrum was a set of complicated multiplets.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH2:13][O:14][C:10]1=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CCCO1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1OCCC1=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Salicylaldehyde (293 g) and γ-butyrolactone (413 g) were dissolved in toluene (2.4 L) and the solution was cooled to not more than 3° C. in an ice-salt bath. Thereto was added sodium methoxide (324 g) over 20 min. The temperature of the reaction mixture rose to 24° C. After stirring at room temperature for 3 hr, the mixture was stirred for 45 min under heating at 60–65° C. The reaction mixture was cooled again in an ice-bath and 10% sulfuric acid (2.51 ml) was added dropwise. The obtained white suspension was filtrated, washed with water and dried to give the title compound (324 g), melting point 162–164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]1([N:32]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]2)[CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[CH2:34][N:32]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:33])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CN(CC1CCCCN1)C1CCCCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN(C)C2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2-(N-cyclohexyl-N-methylaminomethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.25 minutes; C30H37Cl2N5O2 (570.56); mass spectrum: (M−H)−=570/572/574 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+].CC1(C)C(=O)NC2C=CC(N(S(C)(=O)=O)S(C)(=O)=O)=CC=2O1.Cl.C(O)C.O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2NC1=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (1 g) in ethanol (3 mL) was added dropwise an aqueous sodium hydroxide solution (0.18 g/3 mL) at 25° C., then ethanol/water (1:1.2 mL) was added thereto, and the mixture was stirred overnight at the same temperature. To the reaction mixture was added dropwise concentrated hydrochloric acid/ethanol/water (0.24 g/0.5 mL/0.35 mL) at 25° C., and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a solution of ethanol/water (1:1.6 mL), and then dried under reduced pressure at 50° C. to obtain the title compound (0.80 g) as Form B crystals (yield: 98%, purity: 95%).
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl.[CH2:20]([O:32][C:33]([C:35]1[C:36]([C:41](O)=[O:42])=[N:37][CH:38]=[CH:39][N:40]=1)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:20]([O:32][C:33]([C:35]1[C:36]([C:41](=[O:42])[NH:8][C:7]2[CH:1]=[CH:2][N:3]([C@H:9]3[C:10]([F:17])([F:18])[C@H:11]([OH:16])[C@@H:12]([CH2:14][OH:15])[O:13]3)[C:4](=[O:5])[N:6]=2)=[N:37][CH:38]=[CH:39][N:40]=1)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCOC(=O)c1nccnc1C(=O)O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1nccnc1C(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
Gemcitabine hydrochloride (500 mg, 1.67 mmol), 3-(dodecyloxycarbonyl)pyrazine-2-carboxylic acid (674 mg, 2.01 mmol), (Benzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (955 mg, 1.84 mmol), and 4-dimethylaminopyridine (244 mg, 2.0 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water, then extracted three times with ethyl acetate. The isolated organic phase was dried with anhydrous Na2SO4. The solvent was removed by vaporizing under reduced pressure. The residue was purified by silica column chromatography (developing agent; dichloromethane/methanol=40/1) to produce 225.7 mg of dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)pyrazine-2-carboxylate. LC purity 98% (UV 254). LC-MS m/z 582 [M+H]+, (molecular formula: C27H37F2N5O7, molecular weight: 581). The structure and characterization data of the compound were shown in Table 1.