Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([C:10]2[CH:22]=[CH:21][C:13]([C:14]([C:16]([O:18]CC)=O)=[O:15])=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:23][C:24]1[C:25](=O)[O:26][C:27](C)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=1O>C1COCC1>[C:10]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:11]=[CH:12][C:13]([C:14]2([CH3:1])[O:15][C:24](=[O:23])[C:25]([O:26][CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:16]2[OH:18])=[CH:21][CH:22]=1
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Reactant: C[Mg]I
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Yield: 30 %

Procedure:
A total of 3.4 mL (10.2 mmol) of 3.0M methylmagnesium iodide in THF was added to a THF solution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis, 1.1 g (30% yield) of 5-[(1,1'-biphenyl)-4-yl]-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)-furanone as a white granular solid: m.p. 182-183° C. (benzene/hexanes) 1H NMR (CDCl3) δ 7.56-7.26 (m, 14H), 5.10 (ab quartet, 2H, J=11.4 Hz), 1.79 (s, 3H). 13C NMR (CDCl3) δ 168.5, 163.8, 141.5, 140.3, 137.0, 136.3, 129.0, 128.8, 128.8, 128.8, 127.6, 127.2, 127.1, 125.6, 119.0, 81.1, 73.5, 24.3. Anal Calcd for C24H20O4 : C, 77.40; H, 5.41. Found: C, 77.99; H, 5.61.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31](O)=[O:32])=[CH:27][NH:28]2)=[CH:24][CH:23]=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.C(#N)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:26]2[C:25]3[C:29](=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[NH:28][CH:27]=2)=[O:32])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)c[nH]c2c1
Yield: 75.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-6-(methyloxy)-1H-indole-3-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), 6-(methyloxy)-1H-indole-3-carboxylic acid, (0.035 g, 0.18 mmol), HATU (0.1 g, 0.25 mmol), DIPEA (0.05 mL, 0.25 mmol), acetonitrile (3 mL) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.06 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.33 (br. s., 1H), 8.39 (s, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 7.34 (t, 1H), 7.27 (dd, 1H), 7.22 (d, 1H), 6.88 (d, 1H), 6.71 (dd, 1H), 4.43 (d, 2H), 3.74 (s, 3H). MS: m/z 466.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:10](=[O:12])[CH2:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:56][CH2:55]2)[S:52][CH:53]=1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 2,5-dimethylphenylacetic acid (5.45 g, 27.4 mmol) in DMF (80 mL) is added diisopropylethylamine (85.4 mL, 411.32 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (12.8 g, 32.9 mmol) at 0° C. After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester (6.59 g, 27.4 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (500 mL), washed with aqueous saturated sodium bicarbonate solution (500 mL) and the aqueous phase is re-extracted with ethylacetate (100 mL). The combined organic layers are washed with 0.5M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (10.46 g, 98%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=1.41 (t, 3H), 1.52-1.82 (m, 2H), 2.10-2.22 (m, 2H), 2.25 (s, 3H), 2.30 (s, 3H), 2.73-2.86 (m, 1H), 3.08-3.22 (m, 1H), 3.29-3.40 (m, 1H), 3.68 (s, 2H), 3.8-3.95 (m, 1H), 4.38-4.42 (q, 2H), 4.73-4.88 (m, 1H), 6.96 (s, 1H), 6.98-7.01 (d, 1H), 7.08 (d, 1H), 8.10 (s, 1H). MS: m/z=387 (M+1).
Reaction SMILES: [Mg].II.[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.[CH3:15][CH2:16][O:17]CC>>[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7][CH2:15][CH2:16][OH:17]
Reactant: CSc1ccc(Br)c(CBr)c1
Reactant: CCOCC
Agent: II
Agent: [Mg]
Product: CSc1ccc(Br)c(CCCO)c1
Reaction time: 2 h

Procedure:
To a suspension of 25.0 g of magnesium ribbon in a solution of 0.5 g of iodine in 550 ml of anhydrous ether is added 5 ml of a solution of 296.0 g of 2-bromo-5-(methylthio)benzyl bromide in 250 ml of anhydrous ether. The reaction is initiated by gentle heating, and the remainder of the solution is then added dropwise so as to maintain a reflux. Subsequently, the mixture is heated and stirred under reflux for 1 hour, and then cooled to 10°. A stream of nitrogen gas that has been bubbled through a reservoir containing 48.0 g of ethylene oxide is introduced into the reaction mixture. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for 4 hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammonium chloride. Extraction with ether, followed by conventional workup of the ether solution, yield 210.0 g of 3 -(2-bromo-5-(methylthio)phenyl)-1-propanol, bp, about 125°-127° (0.6mm).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][C:22]([O:24]CC)=O.C(O)(=O)C.O>C1(C)C=CC=CC=1>[O:24]=[C:22]1[CH:8]([C:7]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CC/C=C/CCCCCC/C=C/CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)C1C/C=C/CCCCCC/C=C/CCC1=O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CC=CCCCCCCC=CCCC1=O
Temperature: 25 °C

Procedure:
To a flask containing a solution of potassium t-butoxide (6.30 g, 61.1 mmole) in toluene (80 ml), heated to reflux, was added slowly (via syringe pump over 15 hours) a solution of diethyl hexadeca-4E,12E-diene-1,16-dioate (4.32 g, 12.8 mmole) in toluene (10 ml). After the addition was complete the mixture was maintained at reflux for an additional 5 hours. The reaction mixture was cooled to room temperature and to the mixture was added acetic acid and then water. To the mixture was then added diethyl ether, the layers separated and the organic layer was dried with sodium sulfate and evaporated to provide the crude ethyl 15-oxocyclopentadeca-3E,11E-dienecarboxylate which was used directly in the next step. C18H28O3 (292.42 g/mole). 1HNNR (500 MHz, CDCl3): 1.16 (m, 4H), 1.23 (t, 3H), 1.34 (m, 4H), 1.99 (m, 4h), 2.13 (m, 1H), 2.40 (m, 2H), 2.55 (m, 1H), 2.70 (m, 2H), 3.50 (dd, 1H), 4.13 (q, 2H), 5.40 (m, 4H) ppm. 13CNMR (125 MHz, CDCl3): 14.1, 26.2, 27.0, 27.4, 27.7, 28.6, 31.0, 31.1, 31.2, 43.6, 58.4, 61.3, 126.3, 129.1, 131.6, 133.6, 169.5, 204.6 ppm. IR (νmax(cm−1)): 2990, 2940, 2910, 2850, 1745, 1720, 1640, 1440, 1370, 1260, 1040, 970, 860. MS (m/z): 292(M+), 247, 163, 149, 135, 121, 107, 95, 81, 67, 55, 41.
Reaction SMILES: [NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1.Cl>C(Cl)Cl>[NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:10]=[CH:9][CH:2]=[CH:3][CH:4]=1)=[O:5]
Reactant: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Reactant: OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: NC(/C=C(\CCCC(=O)OCc1ccccc1)CP(=O)(O)O)CC(=O)OCc1ccccc1

Procedure:
To 3.25 g (10 mmol) of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate and 10.8 g (100 mmol) of benzyl alcohol are added 10 ml of methylene chloride and 20 ml of 4N ethereal hydrochloric acid, and the mixture is allowed to stand for 1 week. The mixture is then evaporated to dryness, and the residue is dissolved in 25 ml of ethanol. To this solution is then added dropwise a solution of 15 ml of propylene oxide in 15 ml of ethanol. The readily volatile constituents are removed by evaporation under reduced pressure, affording dibenzyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate.
Reaction SMILES: N[C:2]1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[S:30]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1C)(=[O:32])=[O:31]>>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([S:30]([NH:33][C:34]2[CH:35]=[C:36]([CH3:2])[CH:37]=[CH:38][CH:39]=2)(=[O:31])=[O:32])=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1C
Product: COc1cc(N)ccc1S(=O)(=O)Nc1cccc(C)c1

Procedure:
(RK1-1-39) I This compound was prepared according to the procedure described for compound 12a except using 11h to obtain the required product as an orange-brown solid in (169 mg, 66%). Mp: not determined; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 1H), 6.99 (t, J=7.8 Hz, 1H), 6.82 (br s, 1H), 6.79-6.73 (m, 2H), 6.65 (br s, 1H), 6.11 (d, J=2.0 Hz, 1H), 6.09 (s, 1H), 3.99 (br s, 2H), 3.86 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH2:20])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH:20][C:27](=[O:29])[CH3:28])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2cccc([N+](=O)[O-])c2)n2nc(N)nc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(C)cnc(-c3cccc([N+](=O)[O-])c3)n2n1
Reaction time: 1 h

Procedure:
A 12.7 g portion of 8-methyl-5-(3-nitrophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2amine and 306 mg of 4-dimethylaminopyridine in 150 ml of pyridine:acetic anhydride (2:1) was refluxed with stirring for one hour. The solution was cooled and then evaporated to dryness. The residue was slurried in 100 ml of ether and the brown crystals collected. These were dissolved in 1200 ml of hot ethanol, filtered and the filtrate concentrated to 200 ml and cooled. The crystals were collected, giving 11.3 g of the desired product, mp 245°-247° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]2[CH:29]=[C:28]([O:30][CH3:31])[C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)[N:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>O>[ClH:1].[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]3[CH:29]=[C:28]([O:30][CH3:31])[C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc2c1OCO2
Solvent: O
Product: COc1cc(CNCCNc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc2c1OCO2
Product: Cl
Temperature: 140 °C

Procedure:
The operation is carried out as in Stage 3 of Example 7 starting from 65 mg of the product obtained in Stage 1 above, 743 mg of trans-1,4-diaminocyclohexane, the reaction medium is heated to approximately 140° C. for 3 hours, followed by treating with 10 ml of water, extracting with 2×10 ml of ethyl acetate, washing with 10 ml of NaCl (saturated aqueous solution) and drying over MgSO4. Salification is carried out with 1.4N HCL/EtOH, followed by filtering, washing with 5 ml EtOH then drying at ˜50° C. In this way 161 mg of expected product is obtained.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[N:9]=1.[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH3:10][CH:8]1[NH:9][C:3](=[NH:12])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [NH4+]
Reactant: COC1=NC(C)CCCC1
Reactant: [Cl-]
Solvent: CO
Product: CC1CCCCC(=N)N1
Product: Cl
Yield: 74.8 %

Procedure:
The product of EXAMPLE 45 (125 mg, 0.89 mmol) in 9.0 mL of MeOH was reacted with ammonium chloride (44.0 mg, 0.83 mmol) by the method of EXAMPLE 27 to yield 101 mg (63%) of the title material.
Reaction SMILES: O.[Na].[CH3:3][CH:4]([C:7](=O)[CH3:8])[CH:5]=O.[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:7]([CH3:8])=[C:4]([CH3:5])[CH:3]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(C)C=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C#N)c(=O)[nH]c1C
Temperature: 127 °C
Reaction time: 21 h
Yield: 66.4 %

Procedure:
Water was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127° C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65° C. as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24° C., the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9%, m.p. 258-263° C.).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](Cl)(Cl)=[O:19]>C(Cl)Cl.C1C=CC=CC=1>[C:1]([N:5]1[CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[O:17][C:18]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)NCC(O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)N1CC(c2ccc([N+](=O)[O-])cc2)OC1=O
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
In 270 ml of CH2Cl2, 12.97 g of α-[(tertbutylamino)methyl]-p-nitrobenzyl alcohol is dissolved. The solution is cooled to -5° C. and 54 ml of 12.5% phosgene in benzene is added slowly. After the addition is completed, the mixture is stirred for 3.5 hours and poured on ice. The organic phase is separated, and the aqueous layer is extracted with CH2Cl2 (2×100 ml). The combined organic layers are washed with saturated NaHCO3 solution (2×250 ml), 100 ml of H2O and dried over MgSO4. The solution is evaporated to dryness to give 16.3 g, which is recrystallized from MeOH twice to afford 12.58 g of 3-tert-butyl-5-(p-nitrophenyl)-2-oxazolidinone, mp 123°-125° C. This product (10 g) is dissolved in 200 ml of MeOH and hydrogenated over 6 g of Raney nicke at 51 p.s.i.g. at 40° C. to give, after filtration and evaporation, 8.21 g of 5-(p-aminophenyl)-3-tert-butyl-2-oxazolidinone, mp 125°-129° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+]>CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=N)NC(=N)N
Temperature: 40 °C
Yield: 59.8 %

Procedure:
500 g (1 molar equivalent) of metformin hydrochloride and 120.76 g (1 molar equivalent) of sodium hydroxide were stirred in 3750 ml of methanol at room temperature, after which the produced inorganic salt was filtered, and the filtrate was concentrated. The produced crystal was stirred in 5000 ml of acetone at 40° C., and then the produced inorganic salt was filtrated, and the filtrate was concentrated. The produced crystal was stirred in 4000 ml of acetone at 40° C., and then the produced crystal was filtrated, and the filtrate was concentrated, thus obtaining 233.3 g (yield: 59.84%) of metformin free-base.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][CH:28]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH2:30][CH2:29]1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:21][C:22]1[N:26]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[N:24][C:23]=1[CH2:27][CH:28]1[C:40](=[O:41])[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH2:30][CH2:29]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1[nH]cnc1CC1CCc2[nH]c3ccccc3c2C1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 137.7 %

Procedure:
A solution of triphenylchloromethane (4.2 g) in dry DMF (40 ml) was added dropwise to a solution of 1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (3.5 g) and triethylamine (1.75 ml) in dry DMF (35 ml) under nitrogen. After stirring for 4 h the mixture was poured into water (300 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (200 ml), dried and evaporated to give an oil (ca. 9 g) which was purified by FCC eluting with System A (200:10:1) to give the title compound (4.57 g) as a foam, t.l.c. (System A 200:10:1) Rf 0.32.
Reaction SMILES: C([Si](OCCO[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl)(C)C)(C)(C)C.[I-].[Na+].[I-].C[C:22](=[O:25])[CH2:23][CH3:24]>>[CH2:15]([O:14]/[CH:13]=[CH:12]/[CH2:24][CH2:23][CH2:22][OH:25])[CH3:16]
Reactant: CCC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCCl
Agent: [I-]
Agent: [Na+]
Product: CCO/C=C/CCCO

Procedure:
tert-Butyl-{2-[2-(2-chloro-ethoxy)-ethoxy]-ethoxy}-dimethyl-silane was converted to the corresponding iodide by refluxing with 5 equiv of NaI in 2-butanone for 6 h. This was then alkynylated and deprotected by the same process described above to provide E-5-Ethoxy-pent-4-en-1-ol: 1H NMR (500 MHz) 4.02 (q, J=6.8, 2H, H2C(5″)); 3.74–3.70 (m, 2 H, HCO); 3.68–3.66 (m, 2H, HCO); 3.64–3.60 (m, 4H, HCO); 3.54 (t, J=7.3, 2H, H2CO)); 2.49 (t, J=6.3, 1H, OH); 2.41 (t, J 7.3, 2H, H2CO); 1.33 (t, J=7.3, 3H, H3C(6″)); 13C NMR (100 (M+NH4); 186.
Reaction SMILES: C(ONC([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:9]1)=O)C=C.[OH-].[K+].O.NN>C(O)CO.CCOCC>[C:25]1([CH:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH:10]3[CH:11]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[CH2:12][NH:8][CH2:9]3)[CH2:24][CH2:23]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCONC(=O)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: OCCO
Product: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 0.19 g (0.47 mmol) of 1-allyloxycarbamoyl-3-(SR)-(4-phenylpiperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine, 0.52 g (9.4 mmol) KOH and 0.23 mL (4.7 mmol) of hydrazine hydrate in 5 mL of ethylene glycol was heated at 140° C. for 12 h. The reaction mixture was cooled to rt and diluted with ether. The reaction mixture was washed 3 times with H2O, dried over Na2SO4, filtered and the filtrate was concentrated to give 0.13 g of the title compound. 1H NMR (CDCl3) δ7.22-7.37 (m, 7H), 7.04 (d, 1H, J=4.3 Hz), 3.32-3.39 (m, 2H), Mass Spectrum (CI) m/e=327 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([O:13][CH3:14])=[C:2]([CH2:21][C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COc1c(Br)cc(Br)c2ccccc12
Reactant: O=Cc1ccc(Cl)s1
Product: COc1c(Cc2ccc(Cl)s2)cc(Br)c2ccccc12

Procedure:
2,4-Dibromo-1-methoxynaphthalene (see Org. Lett. (2003) 5, 831) and 5-chloro-2-thiophenecarboxaldehyde were treated in a manner similar to Reference Example 1 to give 4-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.O.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:10]([N:9]([CH2:8][C:7]1[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: CCCN(CCC)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1ccc(N)cc1
Temperature: 25 °C
Yield: 38 %

Procedure:
The compound (2.61 g) obtained in Example 15-1 was dissolved in methanol (25 ml). The solution was added with THF (13 ml), activated carbon (261 mg), and iron trichloride hexahydrate (26.1 mg) and the whole was refluxed for 30 minutes. After having been cooled to room temperature, the solution was added with hydrazine monohydrate (1.88 ml) and then the whole was refluxed for 3 hours. After completion of the reaction, the resultant was subjected to filtration through Celite. The filtrate was subjected to extraction with chloroform and washed with distilled water and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (865 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: O=S(=O)(OC[C@@H]1CCCCO1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)(C)OC(=O)C(C[C@@H]1CCCCO1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
570 mg (1.46 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.75 ml (1.75 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 707 mg (purity 87%, 2.48 mmol, 1.7 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate according to General Method 7B. Yield: 396 mg (57% of theory)