Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.CN(C)[CH:49]=[O:50]>C1COCC1.O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH:49]=[O:50])=[CH:7][C:6]=3[C:5]2([CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:13][CH:14]=1
Reactant: CC(C)CCCC(C)CCC1(CCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCC1(CCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame-dried 3-neck round-bottomed flask equipped with a mechanical stirrer and an addition funnel was added 2,7-dibromo-9,9-bis(3,7-dimethyloctyl)fluorene (Example 6; 79.3 g, 131.2 mmol) and THF (350 mL) by cannula. The solution was cooled to −78° C. and 2.5 M n-BuLi in hexane (52.5 mL, 131.2 mmol) was added by addition funnel over 15 min. After stirring for 30 min, N,N-dimethylformamide (DMF, 20.0 mL, 262 mmol) in THF (30 mL) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. Toluene and water were added, and the organic phase was further washed with water, dried with MgSO4, and concentrated. The crude product was purified by column chromatography eluting with heptane to 20% toluene/heptane to give 54 g (75%). 1H NMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.88-7.79 (m, 3H), 7.63 (m, 1H), 7.51 (m, 2H), 1.41 (m, 2H), 1.20-0.93 (m, 12H), 0.92-0.75 (m, 14H), 0.66 (m, 6H), 0.60-0.30 (m, 4H). Mass Spec. m/z 552, 554 (M+). Anal. Calcd. for C34H49BrO: C, 73.76%; H, 8.92%; Br, 14.43%. Found: C, 73.80%; H, 8.86%; Br, 14.64%.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][C@H:33]1[C:37]2([CH2:39][CH2:38]2)[CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:35]2[CH2:34][C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:37]3([CH2:38][CH2:39]3)[CH2:36]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(F)c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (48.7 mg, 0.145 mmol), (7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (45.7 mg, 0.215 mmol), triethylamine (30.8 mg, 0.304 mmol) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 58%. Also, residual ratio of the starting material was 29%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]#[N:17].[C:18](#[N:20])[CH3:19]>CO.N>[CH3:19][C:18]1[N:20]=[C:16]([NH2:17])[C:3]2[N:4]=[CH:5][N:6]([C:2]=2[N:1]=1)[C@@H:7]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: CC#N
Reactant: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Agent: N
Solvent: CO
Product: Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 180 °C
Yield: 35.9 %

Procedure:
10 g of 5-amino-1-β-D-ribofuranosyl-4-imidazolecarbonitrile was dissolved in 20% ammonia methanol solution. 10 ml of acetonitrile was added thereto and the solution was heated for 5 hours at 180° C. The solvent was distilled off, purified by silica gel column chromatography and recrystallized from methanol to give 4.2 g of 2-methyladenosine (yield: 35.9%). 2-methyladenosine was methylated in the same manner as the above-mentioned [METHOD 1] to give Compound 5 and Compound 6.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:40]5[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: OC1CCNCC1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCC(O)CC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((4-hydroxypiperidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and 4-hydroxypiperidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2F)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(F)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 61) according to the procedure of Example 63 as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.56-1.62 (m, 2H), 2.04 (m, 2H), 2.63-2.75 (m, 5H), 2.86-2.95 (m, 4H), 3.01-3.10 (m, 4H), 4.50-4.55 (m, 1H), 5.33 (brs, 1H), 6.57-6.65 (m, 2H), 6.84-7.09 (m, 3H), 8.22 (s, 1H), 7.22-7.29 (m, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 530.0 (MH+); HRMS Calcd. for C25H29FN5O5S(MH+): 530.1873. Found: 530.1876.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CN2CCOCC2)n1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [6-(morpholin-4-ylmethyl)pyridin-2-yl]carbamate (114 mg, 0.39 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol) at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate was added to adjust to pH˜9. The mixture was extracted with ethyl acetate (3×), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 6-(morpholin-4-ylmethyl)pyridin-2-amine that was used without further purification. MS ESI calc'd for C10H16N3O [M+H]+ 194. found 194. 1H NMR (500 MHz, DMSO-d6) δ 7.32 (t, J=7.7 Hz, 1H), 6.52 (d, J=7.2 Hz, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.90 (s, 2H), 3.63-3.49 (m, 4H), 3.40-3.25 (m, 2H), 2.41 (s, 4H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOC1.Cl[CH2:53][CH2:54][CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C(OCC)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:53][CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[N:10]=[CH:9]1
Reactant: ClCCCC1CCCCC1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1nc(CCCOCCCC2CCCCC2)c[nH]1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: O.Cl.C(N1CC(C2C=CC([Cl:37])=C(Cl)C=2)(CCN2CCC(O)(C3C=CC=CC=3)CC2)[O:13]CC1=O)C1C=CC=CC=1.[CH2:40]([N:47]1[CH2:52][C:51]([CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][C:66]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(O)[CH2:65][CH2:64]2)([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.C1(S(O)(=O)=O)C=CC=CC=1.C1(C2([NH:100][C:101]([N:103]3[CH2:107][CH2:106][CH2:105][CH2:104]3)=[O:102])CCNCC2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:13].[ClH:37].[CH2:40]([N:47]1[CH2:52][C:51]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)([CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][C:66]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)([NH:100][C:101]([N:103]3[CH2:107][CH2:106][CH2:105][CH2:104]3)=[O:102])[CH2:65][CH2:64]2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Reactant: O=C(NC1(c2ccccc2)CCNCC1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1COC(CCN2CCC(NC(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Temperature: 90 °C
Yield: 83.2 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.2 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine benzenesulfonate and 0.95 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 3 hours. After cooling to RT, the reaction mixture is poured into water and the precipitate formed is wrung, washed with water and dried under vaccum. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/2; v/v to 100/3; v/v) as the eluent. The product obtained is dissolved in the minimum amount of DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.54 g of the expected product. M.p.=158-160° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)=[O:6]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 5 °C
Yield: 73 %

Procedure:
To a 22 L open-mouth round bottom flask fitted with a three-necked flange head, a mechanical stirrer, a nitrogen inlet and an outlet connected to a HCl scrubbing tower was added 2,5-dichlorobenzoic chloride (4500 g, 21.5 mol) and phenyl ether (5489 g, 32.3 mol). The solution was cooled in ice to 5° C. under stirring and aluminum chloride (3700 g, 27.8 mol) was added slowly. After about 300 g aluminum chloride was added, the solution started to foam violently. The rest was added carefully over about 10 min. On several occasions, the stirring had to be stopped to control the foaming. The temperature of the reaction mixture was about 35° C. after the addition. The mixture was then stirred for about 30 min. and poured into about 20 gallon of ice water. The large reddish mass was dissolved by adding about 12 L of methylene chloride and stirring. The organic layer was separated and the aqueous layer was extracted with some methylene chloride. After methylene chloride was removed from the combined organic layer by distillation, the residue was recrystallized twice from cyclohexane (2×10 L), washed with cooled hexane, air dried and then vacuum dried to afford 5387 g monomer (73%). The mother liquor was kept for later recovery of remaining product.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:24]
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (80 g., 0.036 mole) with p-toluoyl chloride (6.2 g., 0.04 mole) in 50 ml. of pyridine according to the method of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-p-toluanilide. Crystallization from isopropyl ether and then from isopropyl alcohol provides 3.9 g., (32%) of analytically pure material, m.p. 90.5- 92°C. (corr.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#N)=[CH:17][CH:16]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:52])C>CCCCCC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[O:52])=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a mixture of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile (4.18 g) and anhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 23.4 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 15 min. Ethyl acetate was added to the mixture and, after stirring the mixture at room temperature for 30 min., insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.35 g, 56%) of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 101-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17]([NH:24][CH3:23])=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2COc3cc(F)c(F)cc3C2=O)cc1
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc2c(cc1F)C(=O)N(Cc1ccc(OC)cc1)CO2
Temperature: 120 °C
Yield: 85.4 %

Procedure:
To 3-(4-methoxybenzyl)6,7-difluor-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1.15 g, 3.7 mmol) in dimethyl sulfoxide (10 mL) was added methyl amine (2.5 mL, 5 mmol, 2M solution in tetrahydrofuran) and the reaction heated to 120° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 1 g (85%) of 3-(4-methoxybenzyl)6-fluoro-7-(methylamino)2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.82 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 7.6 (d, 1), 6.8 (d, 2), 6.4 (d, 1H), 5.0 (s, 2), 4.6 (s, 2), 3.7 (s, 3), 2.8 (s, 3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([CH2:13][OH:14])[CH2:10][CH:9]1[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCCCCC.C(OCC)(=O)C.S(=O)(=O)(O)O>ClCCl.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3]>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([CH:13]=[O:14])[CH2:10][CH:9]1[CH:11]=[CH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(CO)NC(=O)OC(C)(C)C
Agent: O=[Mo](=O)([O-])[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CC1CC1(C=O)NC(=O)OC(C)(C)C
Yield: 35.9 %

Procedure:
To a stirred solution of the alcohol 19a (0.152 g, 0.71 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (0.33 g, 0.78 mmol) at rt. The reaction was monitored by TLC (3:2 Hexane-ethyl acetate, UV-monitoring and staining using ammoniummolybdate-cerium sulfate in aq. 10% sulfuric acid). Staining indicates a fairly clean reaction, but UV monitoring indicates several byproducts. After 1 h the obtained yellow-red solution was diluted with dichloromethane (20 ml), then washed with 1:1 aq. 10% sodium thiosulfate/aq. saturated sodium hydrogen carbonate (3×20 ml), then dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue using stepwise gradient elution (ethyl acetate in hexane 20-30%) followed by concentration of the appropriate fractions and drying the residue in vacuum overnight, gave the title compound as a colorless oil (0.054 g, 0.255 mmol, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].C1(=O)O[CH2:32][CH2:31][O:30]1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:32][CH2:31][OH:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1OCCO1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CCO
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione and 30 ml of dimethylformamide was added 0.53 g of 55 % sodium hydride, and the solution was heated up to 150°C. To this was added 0.97 g of ethylene carbonate, and the mixture was reacted for one hour at 150°C. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.8 g of 1-(m-nitrophenyl)-3-(2-hydroxyethyl)pyrido[2,3-d] pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 212°-213°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr

Procedure:
To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl4 (150 mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl4 was removed under reduced pressure and the residue was diluted, dissolved in ether, washed with brine (3×), dried over MgSO4, and concentrated. Chromotography in hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:1](=[C:11]1/[C:10](=[O:15])[CH2:14][CH2:13][CH2:12]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC/C=C1\CCCC1=O

Procedure:
The procedure was similar to that in Example 1 by reacting n-octanal with cyclopentanone in the presence of 1% NaOH to give 2-(E)-octylidene cyclopentanone. The boiling point of this intermediate compound was determined to be 120°-125° C. at a pressure of 4 mm Hg. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-octylidene cyclopentanone hydrochloride. The melting point of the product was determined to be 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[Li]CCCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl.OP([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([B:28]([OH:29])[OH:27])=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(B(O)O)cc2c(Cl)ccnc21
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (565 mg, 2 mmol) in THF (5 mL) at −40° C. under N2, was added n-BuLi (2.0 M in cyclohexane, Aldrich, 2.4 mmol). The reaction mixture was stirred at −40° C. for 1 h and then treated with triisopropylborate (489 mg, 2.6 mmol). The mixture was slowly warmed to rt and stirred overnight. To this solution was added 1 N HCl in H2O (20 mL), and the mixture was stirred for 20 min., neutralized with saturated aq. K2HPO4 solution and extracted with ether. The organic layer was dried over Na2SO4. After filtration and concentration under reduced pressure, the title compound was obtained as a light beige solid (640 mg, quantitative yield). LC/MS(ESI+) m/z 327 (M+H)+.