Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][S:30]([NH:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])([CH3:6])[CH3:7])(=[O:32])=[O:31])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCNC(=O)c1nc(Cl)c(N)nc1N)CCNS(=O)(=O)Cc1ccc(Cl)cc1

Procedure:
A solution of (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) (0.3 g, 0.78 mmol), (4-chloro-phenyl)-methanesulfonyl chloride (0.18 g, 0.78 mmol) and N-methylmorpholine (0.35 mL, 3.18 mmol) in DMF (5 mL) is shaken at RT for 16 h. After this time the solvent is removed in vacuo and the residue is subjected to chromatography (basic alumina, 0-15% methanol in DCM) to yield the title compound. M+ 490.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(C(C)C)C(C)C.[Si:31]([O:38][C@@H:39]1[C@@H:43]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[O:42][C@@H:41]([N:53]2[C:62]3[N:61]=[CH:60][N:59]=[C:57]([OH:58])[C:56]=3[N:55]=[CH:54]2)[CH2:40]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[CH:63]1[CH:64]=[CH:65][C:66]2[N:71](O)[N:70]=[N:69][C:67]=2[CH:68]=1>C(Cl)Cl>[N:69]1([O:58][C:57]2[C:56]3[N:55]=[CH:54][N:53]([C:62]=3[N:61]=[CH:60][N:59]=2)[C@@H:41]2[O:42][C@H:43]([CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:47])[CH3:48])[C@@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[CH2:40]2)[C:67]2[CH:68]=[CH:63][CH:64]=[CH:65][C:66]=2[N:71]=[N:70]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
In a 50 mL round-bottom flask equipped with a stirring bar were placed PPh3 (0.823 g, 3.138 mmol) and I2 (0.800 g, 3.152 mmol) in dry CH2Cl2 (11.0 mL) and the mixture was stirred at room temperature for 20 min. DIPEA (1.5 mL, 8.62 mmol) and 3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (1a) (0.500 g, 1.040 mmol) were added, and the mixture was allowed to stir at room temperature for 26 h. To this mixture was added HOBT (0.211 g, 1.561 mmol) and the reaction was allowed to continue and was complete in 22 h. The crude material was evaporated and chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 0.578 g (93%) of compound 26 as a beige foam.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=3)=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A mixture of tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.015 g, 0.030 mmol), nicotinoyl chloride hydrochloride (0.007 g, 0.039 mmol), and triethylamine (0.013 ml, 0.091 mmol) in dichloromethane (1 ml) was stirred at ambient temperature for 1 hour. The reaction was loaded onto a silica gel samplet and the product was eluted using a gradient system of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to provide tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetate (0.005 g, 275%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:31].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:2]2=[O:1])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.55 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.38 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.073 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.7 g, 90%).
Reaction SMILES: [CH3:1][C:2](CCCC(C)COC1CCCCO1)=[CH:3][CH2:4][CH:5]([O:15][C:16](=[O:18])[CH3:17])C(C)=CC1N=C(C)SC=1.C(OC(CC=C(C)CCCC(C)COC1CCCCO1)C(=O)C)(=[O:34])C>>[C:16]([O:15][CH2:5][C:4](=[O:34])[CH2:3][CH2:2][CH3:1])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=Cc1csc(C)n1
Reactant: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Product: CCCC(=O)COC(C)=O

Procedure:
MS (CI): m/z (%)=43 (39), 45 (22), 57 (34), 91 (19), 119 (10), 145 (9), 173 (9), 189 (14), 190 (78), 191 (18), 233 (45), 246 (22), 251 (100), 252 (11), 307 (44).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[C:7](O)[CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1.[O-]S(C(F)(F)F)(=O)=O.[CH2:19](N(CC)CC)[CH3:20]>ClCCl>[C:19]([C:7]1[CH:8]=[CH:9][C:4]2[N:5]([N:1]=[CH:2][CH:3]=2)[CH:6]=1)#[CH:20]
Reactant: Oc1ccc2ccnn2c1
Reactant: CCN(CC)CC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C#Cc1ccc2ccnn2c1

Procedure:
A 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID can be obtained by decarboxylation of an appropriately substituted 6-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid ester 22 with hydrobromic acid, yielding the corresponding pyrazolo[1,5-a]pyridin-6-ol derivative 23, which is converted to the triflate derivative 25 using trifluoromethanesulfonic anhydride 24 and a base such as triethylamine in a solvent such as dichloromethane. Sonogashira coupling of 25 with an aryl-acetylene of formula 3 yields the desired 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID (scheme 5).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:19](=[O:48])[NH:20][CH:21]([C:26](=[O:47])[N:27]([CH:29]([CH:44]([CH3:46])[CH3:45])[CH:30]=[C:31]([CH3:43])[C:32]([C:34]1[N:35](COCC)[CH:36]=[CH:37][N:38]=1)=[O:33])[CH3:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:35]1[CH:36]=[CH:37][N:38]=[C:34]1[C:32](=[O:33])/[C:31](/[CH3:43])=[CH:30]/[C@@H:29]([N:27]([CH3:28])[C:26](=[O:47])[C@@H:21]([NH:20][C:19](=[O:48])[C@@H:9]([NH:7][CH3:6])[C:10]([CH3:11])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:18])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:44]([CH3:46])[CH3:45]
Reactant: CCOCn1ccnc1C(=O)C(C)=CC(C(C)C)N(C)C(=O)C(NC(=O)C(N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)c1ncc[nH]1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
[1-(1-{[4-(-Ethoxymethyl-1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxo-but-2-enyl]-methyl-carbamoyl}-2,2-dimethyl-propylcarbamoyl)-2-methyl-2-phenyl-propyl]-methyl-carbamic acid tert-butyl ester (45 mg, 0.066 mmole) is treated with 2 ml trifluoroacetic acid in 2 ml dichloromethane at room temperature for 2 hours. The solvent is evaporated and pumped in oven overnight to give 8 mg white solid product, (2S)-N-[(1S,2E)-4-(1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxobut-2-enyl]-N,3,3-trimethyl-2-{[(2S)-3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanamide: 8 mg (16%). MS (ES+): (M+H)=524.4
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14]C)=O)[CH:3]=1.[NH2:16][OH:17].Cl>CO>[OH:17][NH:16][C:12]([C:4]1[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)=[O:14]
Reactant: NO
Reactant: COC(=O)c1cc(S)n2nc(C)nc2n1
Agent: Cl
Solvent: CO
Product: Cc1nc2nc(C(=O)NO)cc(S)n2n1
Yield: 107.5 %

Procedure:
Methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (500 mg) (2.23 mmol) are suspended in 10 ml of absolute methanol. 2.95 mg (8.9 mmol) of hydroxylamine are added within 4 days while stirring. The reaction mixture is acidified (pH 6) with 3N aqueous hydrochloric acid. The product is filtered off under suction and washed in sequence with water, methanol and diethyl ether. There are obtained 540 mg of N-hydroxy-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxamide as yellow crystals of melting point 178°-179° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1nnc(C)s1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1nnc(C)s1
Yield: 71.2 %

Procedure:
Ethyl 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)-acetate (syn isomer) (0.4 g.) and 1N aqueous solution of sodium hydroxide (2.1 ml.) were treated according to a similar manner to that of Example 1(a)(5) to give 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (syn isomer) (0.25 g.), mp 168° to 171° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-33.5°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11]C(=O)OC(C)(C)C)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[N:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([I:10])[CH:9]=1)[NH2:11])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)cc(N=[N+]=[N-])c1
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(N)cc(I)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Step A-4. To a stirred solution of 3-azido-5-iodophenylcarbamic acid, 1,1-dimethylethyl ester (A-3, 4.03 g, 11.2 mmol) in dichloromethane (13 mL) is added trifluoroacetic acid (13 mL). The reaction mixture is stirred at 20°-25° C. for 30 minutes and then carefully poured into a stirred mixture of saturated aqueous bicarbonate (300 mL) and dichloromethane (300 mL). The phases are separated and the organics are dried (MgSO4), filtered and concentrated. The residue is purified by medium pressure liquid chromatography using 20% ethyl acetate in hexane as the eluent to afford 2.43 g of 3-azido-5-iodoaniline (A-4) which is used immediately in the next reaction, CHART B, Step B-1. A small analytical sample is recrystallized from ethyl acetate in hexane. Mp=89°-91° C. IR (mull) 3402, 3299, 2954, 2925, 2869, 2135, 2119, 1596, 1581, 1572, 1570, 1463, 1149, 1304, 1246, 987, 842, 826 cm-1 ; 1H NMR (CDCl3) δ6.79 (t, 1 H, J=2 Hz), 6.75 (t, 1 H, J=3 Hz), 6.23 (t, 1 H, J=2 Hz), 3.75 (bs, 2 H); 13C NMR(CDCl3) δ148.5, 141.9, 120.3, 117.7, 104.6, 94.9; Mass Spec (70eV, EI) m/z 260 (parent), 232, 205, 165, 127, 116, 105 (base), 78, 66, 541, 37; Exact mass calculated for C6H5IN4 : 259.9561. Found: 259.9573. Analysis calculated for C6H5IN4 ; C, 27.71; H, 1.90; N, 21.55; Found C, 27.67; H, 1.90; N, 21.66.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])[CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>CC#N.CCN(CC)CC.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.[Cu]I>[CH3:11][O:10][CH2:9][C:8]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:7]=[CH:6][CH:5]=1)([CH3:13])[CH3:12]
Reactant: COCC(C)(C)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of 1-bromo-3-(2-methoxy-1,1-dimethyl-ethyl)-benzene (1.62 g, 6.69 mmol) and trimethylsilylacetylene (1.2 mL, 8.7 mmol, 1.3 eq.) in MeCN-Et3N (50 mL, 7:3) was added Pd(PPh3)2Cl2 (0.23 g, 0.33 mmol. 0.05 eq.), CuI (0.038 g, 0.2 mmol, 0.03 eq.) and the mixture refluxed for 16 h. After cooling to ambient temperature and concentration under reduced pressure the residue was chromatographed (EtOAc-hexane, 2:98) to obtain 1.54 g (89%) of the desired product. NMR (DMSO-d6): 7.28-7.00 (m, 4H), 3.16 (s, 2H), 2.98 (s, 3H), 1.00 (s, 6H), 0.1 (s, 9H). MS (DCI): 261 (M+1).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=S.[Br:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]2[NH:13][C:2]([NH:1][CH3:4])=[N:12][C:10]=2[CH:11]=1
Reactant: CN=C=S
Reactant: Cc1cc(Br)cc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc2cc(Br)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].C(#N)C>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COc1cc2c(cc1C)[C@]1(CO2)C(=O)Nc2ccccc21

Procedure:
6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g, 0.10 g per run) was resolved on a semi-prep chiral IA column with 10% acetonitrile in tert-butyl methylether. (R)-6-methoxy-5-methyl-2H-spiro[benzofuran-3,3′-indolin]-2′-one was isolated as a crystalline colorless solid (0.81 g, 75% recovery): ee>99% (analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether); mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.57 (s, 1H), 7.23 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s, 1H), 1.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.1 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])(=[O:15])[CH3:14]>>[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])(=[O:15])[CH3:14]
Reactant: CCCCCCC(C/C=C\CCCCCCCC(=O)Cl)OC(C)=O
Reactant: O=C(OCCO)c1ccccc1
Product: CCCCCCC(C/C=C\CCCCCCCC(=O)OCCOC(=O)c1ccccc1)OC(C)=O

Procedure:
2-Benzoyloxyethyl 12-acetoxyoleate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 36 gms (0.1 mole) of 12-acetoxyoleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[CH2:18](I)[CH3:19]>>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:18][CH3:19])[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Product: CCc1cc2c(=O)c(C(=O)O)cn(CC)c2s1

Procedure:
In a manner similar to that described in Example 13, ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate is reacted with ethyl iodide to obtain 2,7-diethyl-4,7-dihydro-4-oxothieno-[2,3-b]pyridine-5-carboxylic acid. Recrystallization from methanol gives colorless prisms melting at 197°-198° C.
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[F:6][C:7]1[CH:15]=[CH:14][C:10](C[Mg]Cl)=[CH:9][CH:8]=1.CCCCCC>C1COCC1>[Cl:5][Si:2]([CH3:3])([CH3:4])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: Fc1ccc(C[Mg]Cl)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(Cl)c1ccc(F)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
First, 6.45 g of dichlorodimethylsilane was dissolved in dry THF and cooled to 0° C. Next, 100 ml of 4-fluorobenzylmagnesium chloride (0.25M) was slowly added dropwise thereto. After the completion of the addition, the reaction mixture was allowed to further react at low temperature for about 3 hours. Next, an excessive amount of hexane was added to the reaction mixture to precipitate a magnesium salt. The magnesium salt was removed via filtration and the organic solvent was evaporated under reduced pressure. By doing so, chlorodimethyl(4-fluorophenyl)silane was obtained with a yield of 80% via vacuum distillation. In a separate container, 3.0 g of 4-bromo-4′-n-propylbiphenyl and 250 mg of Mg was added to 20 ml of dry THF to provide a Grignard reagent, to which 2.3 g of chlorodimethyl(4-fluorophenyl)silane was added at room temperature. The reaction mixture was heated to 60° C. for about 10 hours, and worked up with water and hexane, and then purified by silica gel column chromatography to obtain the silicon-containing compound represented by the above formula (yield: 91%). 400 MHz 1H-NMR, CDCl3, δ (ppm): 0.30 (s, 6H), 0.99 (t, 3H), 1.65˜1.74 (m, 2H), 2.30 (s, 2H), 2.65 (t, 2H), 6.89 (d, 4H), 7.26˜7.28 (m, 2H), 7.50 (d, 2H), 7.54 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:13][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCSCCCC
Reactant: Cc1ccccc1I
Product: CCCCSc1ccccc1C

Procedure:
The general procedure was used to convert 2-iodotoluene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (331 mg, 93% yield). 1H NMR (300 MHz, CDCl3) δ 7.17–6.97 (m, 4H; Ha, Hb, Hc, Hd), 2.80–2.78 (t, J=7.3, 2H; Hf), 2.27 (s, 3H; He), 1.61–1.51 (m, 2H; Hg,), 1.44–1.17 (m, 2H; Hh), 0.87–0.82 (t, J=7.3, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 137 (C1), 136.3 (C6), 129.9 (C5), 127.1 (C2), 126.2 (C3), 125.1 (C4), 32.3 (C8), 31 (C9), 22 (C10), 20.2 (C7), 13.6 (C11). Anal. Calcd. for C11H16S: C, 73.27; H, 8.94; S, 17.78; Found C, 73.23; H, 9.16, S, 17.57.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[OH:16][C@H:14]1[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:11])[CH2:13]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of (4R)-1-(tert-butoxy carbonyl)-4-hydroxy-L-proline in DMF (80 ml) was added 5.4 g of NaHCO3 and 11.1 g of benzyl bromide and the reaction mixture was stirred at 60° C. for 5 hours. Water was added to the reaction solution and the resulting mixture was extracted with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: hexane/EtOAc=1/1 to CHCl3/MeOH=8/1; v/v) to obtain 10.0 g of the title compound (colorless oil).