Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:9][C:10]([Br:12])=[CH2:11])[C:5]([O:7][CH3:8])=[O:6].CC(C)([O-])C.[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:9][C:10]([Br:12])=[CH2:11])([C:3]([O:2][CH3:1])=[O:13])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: C=C(Br)CC(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(Br)CC(CC(=O)OC(C)(C)C)(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
The title compound of Example 1A (0.5 g, 2 mmol) dissolved in THF (20 mL) was cooled to 0° under nitrogen. Potassium tert-butoxide (0.25 g, 2.2 mmol) was added all at once. After a further 20 min, tert-butyl bromoacetate (0.39 g, 2.2 mmol) was added dropwise from a syringe. The reaction mixture was stirred 16 h at room temperature. The excess base was destroyed by the addition of wet THF (2 ml) followed by the addition of H2O (40 mL) and EtOAc (40 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The crude oil was purified by column chromatography (SiO2) to give the title compound (0.619 g, 85% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ5.64 (broad s, 1H), 5.59 (broad s, 1H,), 3.75 (s, 6H), 3.35 (s, 2H), 3.07 (s, 2H), 1.43 (s, 9H); 13CNMR (100 MHz, CDCl3) δ169.42, 168.43, 127.16, 122.35, 81.29, 54.64, 52.91, 43.53, 37.25, 27.92.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:29])=[O:5])[CH3:2].ClCCl>>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:29])[C:8]2([CH2:21][C:22]([OH:24])=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)(C(=O)OCC)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)C(CC(=O)O)(C(=O)OCC)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of diethyl-3-(2-tert-butoxy-2-oxoethyl)-5-chloro-2-oxoindoline-1,3-dicarboxylate, intermediate 51, (1.83 g, 4.30 mmol) in dichloromethane (30 ml) trifluoroacetic acid (3.18 ml, 42.97 mmol) was added at 0-5° C. Stirring was continued at 0-5° C. for 30 minutes and at ambient temperature overnight. Evaporation and drying under high vacuum gave the title compound (1.57 g, 99%) as colorless oil (HPLC purity: 85%). MS (ESI+): 370.2
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2].[Fe:12](Cl)([Cl:14])[Cl:13].C(O)C>CCOCC>[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:12].[Fe:12]([Cl:14])[Cl:13]
Reactant: Cl[Fe](Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCO
Solvent: CCOCC
Product: Cl[Fe]Cl

Procedure:
Impure ferricenium tetrachloroferrate is prepared from ferrocene (2 mmol) and anhydrous iron(III) chloride (4 mmol) in ether, with recrystallization from absolute ethanol, by the process of Nesmeyanov et al. The product obtained, the infrared spectrum of which shows that it is a product contaminated with diferricenium μ-oxo-bis(trichloroferrate), can be recrystallized either from freshly distilled thionyl chloride or from 0.15-0.25M aqueous-methanolic (2:98) hydrogen chloride, a ferricenium tetrachloroferrate which is pure according to spectroscopy (disappearance of the maxima at 365 and 316 cm-1) and elemental analysis being obtained in the form of blue-black crystal flakes. Found: C, 31.22; H, 2.71; Cl, 36.80. Calculated for C10H10Cl4Fe2 : C, 31.30; H, 2.63; Cl, 36.96. The recrystallization from the acid medium can also be carried out directly with the crude product obtained from ferrocene and iron chloride, by-avoiding the recrystallization from absolute ethanol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[N:9]=1)[CH3:3].[OH-].[Li+]>C1COCC1.CO>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)[CH3:1]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-((dimethylamino)methyl)thiazole-4-carboxylate (147 mg, 0.686 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (1.372 ml, 1.372 mmol) was added slowly. The reaction mixture was stirred at RT for 3 h, pH was adjusted to 2 and the mixture was evaporated to dryness to yield the title compound as a crude product. m/z [186.2+1].
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[NH:12][C:11](=[O:28])[C:10]=2[CH:29]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[C:21]1([CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C:13]3([NH:12][C:11](=[O:28])[C:10]4[CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]=4[O:27]3)[CH2:18][CH2:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (292 mg, 0.719 mmol) was suspended in dioxane (5 ml) and water (5 ml). 1 M NaOH (0.93 ml) was added and the resulting mixture was stirred overnight at RT. The mixture was neutralized with 1 M HCl and concentrated under vacuum. The pH was brought to 4 with 1 M HCl and the resulting solid was decanted and dried to give (E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid (265 mg).
Reaction SMILES: [Br-].[PH4+].C1([C:9](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C=CC=CC=1.[H-].[Na+].[CH3:32][C:33]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:34]=1[CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.O>CS(C)=O>[CH2:10]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:40][C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([O:36][CH2:35][C:34]2[C:33]([CH3:32])=[CH:48][CH:47]=[CH:46][C:45]=2[CH3:49])[CH:38]=1)[CH3:9]
Reactant: Cc1cccc(C)c1COc1cccc(C=O)c1
Reactant: CCCCC(=O)OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCC=Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 26.700000762939453 °C
Reaction time: 0.5 h
Yield: 195.1 %

Procedure:
A mixture of triphenylethylvalerate phosphonium bromide (Step A, 13.29 g, 28.2 mmol) and sodium hydride (0.745 g, 31.0 mmol) in dimethyl sulfoxide (40 ml) was stirred for 30 minutes under nitrogen. The reaction mixture was heated to 26.7° C. and 3-(2,6-Dimethylbenzyloxy)benzaldehyde (5.00 g, 20.8 mmol) diluted in dimethyl sulfoxide (20 ml) was added dropwise over 4 minutes. The reaction mixture was stirred for 3 hours at 50° C. A mixture of triphenylethylvalerate phosphonium bromide (Step A, 5.56 g, 118 mmol) and sodium hydride (0.312 g) in dimethyl sulfoxide (15 ml) was stirred under nitrogen for 30 minutes. This mixture was added, in bolus to the above reaction mixture at room temperature. The reaction mixture was stirred for 6 hours at 50° C., cooled to room temperature and poured over ice (60 g) and water (60 ml) mixture. The aqueous mixture was extracted with ethyl acetate (3×150 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the 14.3 g of brown oil. The oil was dissolved in 30 ml of hexane:ethyl acetate (95:5) and chromatographed on a Biotage 75S silica gel column to give 5.8 g of a yellow oil. The yellow oil was subjected to another silica gel column chromatography eluting with hexane:chloroform (1:1) to hexane:ethyl acetate (9:1) to afford 3.74 g (51%) of a dark yellow oil.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].[C].C1(C)C=CC=CC=1>[C:2]1([C:3]2[CH:2]=[CH:5][CH:4]=[CH:5][CH:4]=2)[CH:3]=[CH:2][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C1CCOC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
1.31 g (3 mmol) of II-23 was mixed with 10 ml of tetrahydrofuran, 3 ml of toluene and 0.1 g of 2% Pd-carbon, and the mixture was subjected to catalytic hydrogenation in a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and further treated and purified according to Example 21 to obtain 0.32 g (31% yield) of (+)-4-hydroxy-4'-(1-2's,3's-2-chloro-3-methylpentanoyl)ethyl)biphenyl. [α]D25 =+60° (c=1, CHCl3), m.p.=99°-100° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH3-]C#N.[Na+].[N-]=C=O>C1COCC1.CCO>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (11.0 g, 53.8 mmol) and of tetrahydro-4H-pyran-4-one (5.39 g, 53.8 mmol) at 0° C. was added Ti(IV) isopropoxide (19.2 mL, 67.3 mmol). The resulting mixture was stirred at rt overnight and an orange suspension was obtained. To the suspension was added EtOH (25 mL) and NaCNBH3 (4.27 g, 64.6 mmol, 1.20 eq). The resulting mixture was stirred at rt for 24 h. The reaction mixture was then quenched with water (5.0 mL) and a yellow solid was generated. The suspension was diluted with EtOAc (400 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was again diluted with EtOAc (500 mL), dried over Na2SO4, and filtered. The filtrate was collected and concentrated under reduced pressure to afford a yellow oil. The oil was diluted in THF (400 mL) and PS-isocyanate was added to remove secondary amine. The suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography using 50:5:1 CHCl3/MeOH/Et3N to afford the desired compound as yellow oil (13.0 g, 84%)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:28][CH:29]=[C:30]([C:33]2[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=4)[NH:35][CH:34]=2)[CH2:31][CH2:32]1)[O:14]3
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccc(C#N)cc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1,6 mmole) and 3-(1,2,3,6-tetrahydro4-pyridinyl)-1H-indole-5-carbonitrile (0.85 g, 3.8 mmole) were combined in 70 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 30% hexane/ethyl acetate to remove impurities. Ethyl acetate eluted the product, which was a yellow oil (0.24 g, 42%). The oil was crystallized from ethanol with the addition of a solution of fumaric acid (0.12 g, 1.02 mmole) in hot ethanol to give 0.20 g of the (S)-enantiomer of the title compound as a yellow solid difumarate•0.50 hydrate, m.p. 119° C. MS (ESI) m/z 427 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:6]=1[NH:16][C:17](=[O:19])[CH3:18])#[N:4].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].CN(C)C=O>O1CCCC1.CCOC(C)=O>[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:6]=1[N:16]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:17](=[O:19])[CH3:18])#[N:4]
Reactant: CC(Br)c1ccccc1
Reactant: CC(=O)Nc1nc(N2CCOCC2)sc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)N(c1nc(N2CCOCC2)sc1C#N)C(C)c1ccccc1
Temperature: 50 °C
Yield: 84.9 %

Procedure:
NaH (43.6 mg, 1.090 mmol) was added to a suspension of N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (250 mg, 0.991 mmol) in Tetrahydrofuran (THF) (8 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min. (1-Bromoethyl)benzene (183 mg, 0.991 mmol) was added dropwise. N,N-Dimethylformamide (DMF) (2 mL) was added. The reaction mixture was heated at 50° C. overnight. LCMS showed the reaction was almost completed. EtOAc was added and washed with H2O, brine and dried (Na2SO4). Removal of the solvent followed by flash column chromatography on a 25 g silica column, which was eluted with 50% EtOAc/hexane to give 300 mg of light yellow sticky/foamy solid as the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:2]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]([NH:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:20])[CH:2]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1cnc2ccccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 3-aminoquinoline (64 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-45% EtOAc in hexane), the title compound as a white solid. MP 196-199° C. MS (ESI, pos. ion) m/z: 420 (M+1).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.C([O:15][P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)([O:18]CC)=[O:17])C>CN(C=O)C>[P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])([OH:18])([OH:17])=[O:15]
Reactant: CCOP(=O)(COCCCCBr)OCC
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCOCP(=O)(O)O
Reaction time: 2 h

Procedure:
To a slurry of 0.962 g (22.8 mmol) of 57% NaH in 150 ml of distilled DMF was added in one portion 3.363 gm (24.9 mmol) of adenine. The mixture was heated at 80° for 1 hr. and then cooled to 300 and 6.30 g (20.7 mmol) of 4-(diethylphosphonomethoxy)-1-bromobutane was added and the mixture was warmed to 60° and stirred for 2 hrs. The solvent was then removed under high vacuum and the residue was triturated three times with 100 ml of CH2Cl2 and filtered. The combined filtrates were evaporated and purified by SiO2 chromatography to give 4.9 g (66%) of Ia product as a white crystalline material mp 67°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:4]=2[O:3][CH2:2]1.[N+:12]([CH3:15])([O-:14])=[O:13]>>[N+:12]([CH:15]=[CH:10][C:9]1[C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2c1OCO2
Product: O=[N+]([O-])C=Cc1cccc2c1OCO2

Procedure:
In close analogy to the procedure described above, Benzo[1,3]dioxole-4-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:12][C@H:11]2[C@H:7]([CH2:8][C:9](=[O:13])[O:10]2)[C@H:6]1[CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[CH2:17]1[CH2:18][O:19][CH:15]([CH2:14][C@H:6]2[C@H:5]([OH:4])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:13])[O:10]3)[O:16]1
Reactant: CC(=O)O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1CC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1C[C@@H]2[C@@H](CC3OCCO3)[C@H](O)C[C@@H]2O1

Procedure:
The acetal (55) (4.180 g) was treated with potassium carbonate (1.18 g) in methanol (100 ml) at room temperature for 2 hours with stirring. The reaction mixture was neutralized with addition of acetic acid, followed by the usual work up to give a crude product. The crude product was chromatographed on a column of silica gel to give the alcohol (56).
Reaction SMILES: [NH:1]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[C:10]([O:12]CC)=O)[C:2]([NH2:4])=[O:3].[OH-].[Na+].Cl>CO>[N:1]1[C:5]2[CH:9]=[CH:8][O:7][C:6]=2[C:10]([OH:12])=[N:4][C:2]=1[OH:3]
Reactant: CCOC(=O)c1occc1NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc(O)c2occc2n1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Ethyl 3-ureidofuran-2-carboxylate 35 (120 mg, 1.0 eq) was suspended in methanol (6 ml) and treated with 1.5 M NaOH (1.5 ml). Reaction mixture was heated to reflux for 90 minutes. Reaction mixture was allowed to cool down to room temperature, and was acidified with 6N HCl up to pH 3. Mixture was concentrated. Methanol was added to residue and solid was filtered and dried at 95° C. under high vacuum for 24 h to yield furo[3,2-d]pyrimidine-2,4-diol 36 (90 mg, 91%) which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:10]1[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=[CH:13][N:14]=1)[OH:9].BrC1C=CC(C(C2C=CC=CC=2)(C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CN=2)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:10]1[NH:14][CH:13]=[CH:12][N:11]=1)[OH:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccccc2Cl)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Br)cc2)cc1
Product: OC(c1ccccc1)(c1ncc[nH]1)c1ccccc1Cl

Procedure:
Using the procedure described in Example IB but substituting an equivalent amount of α-(o-chlorophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol for the α-(p-bromophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol, α-(o-chlorophenyl)-α-phenylimidazole-2-methanol was obtained. Its melting point was 186°-188° C. after crystallisation from isopropyl alcohol.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=C2CCCCN2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:10]3[CH2:37][CH2:36][C:7](=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Fc1ccc(C(=C2CCCCN2)c2ccc(F)cc2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(bis(4-fluorophenyl)methylenepiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 88% overall yield. FDMS m/e=474 (M+ of free base). α[D]589 =-8.49 (c=0.71, methanol).
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36])([O-:31])=[O:30].O>C(Cl)Cl>[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:35]([C:34]1[CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:40]=[CH:39][CH:38]=1)=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCNCCCCCCCCCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc([N+](=O)[O-])c1
Yield: 83.2 %

Procedure:
To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamine and 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylene chloride was added dropwise a solution of 0.50 g (2.69 mmol) of 3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. The mixture was stirred at room temperature for 4 hours. Water was added, the organic layer was separated and dried. The solvent was removed at reduced pressure and the residual oil was purified by chromatography on 30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium on carbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under a hydrogen atmosphere at room temperature for 2 hours when hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]2[NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=3)=[N:21][C:15]=2[CH:14]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: N#Cc1ccc(C=O)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc(C#N)c(F)c3)[nH]c2cc1C
Yield: 65.2 %

Procedure:
To a solution of 2-fluoro-4-formylbenzonitrile 1 (100 mg, 0.7 mmol) and 4,5-dimethyl benzene-1,2-diamine 2 (109 mg, 0.8 mmol) in ethanol (10 ml) was added a catalytic amount of p-toluenesulfonic acid (0.5 mg, 0.5 mmol). The mixture was stirred reflux for 2 hours and concentrated by rotor evaporation. The crude material was purified through column chromatography with 40% ethyl acetate in hexane to yield compound 3 as white solid (68% yield, 121 mg, confirmed by LCMS: 266.20).
Reaction SMILES: C([NH:4][C:5]1[C:24]([Cl:25])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH:22]3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16][CH2:15][CH2:14]2)=[O:10])=[C:7]([O:26][CH3:27])[CH:6]=1)(=O)C>C(Cl)Cl>[NH2:4][C:5]1[C:24]([Cl:25])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH:22]3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16][CH2:15][CH2:14]2)=[O:10])=[C:7]([O:26][CH3:27])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CCCN2CCCCC12
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCCN2CCCCC12

Procedure:
Following the procedures outlined in Example (2), the isomer mixture of (±) 4-acetamido-5-chloro-2-methoxy-N-(1'-quinolizidinyl-methyl)-benzamide (4.0 g) was converted to the crude product. Chromatography on Brockman II basic alumina (200 g), using methylene chloride as eluant, afforded one of the isomers (A, 0.9 g, 15%) of (±) 4-amino-5-chloro-2-methoxy-N-(1'-quinolizidinyl-methyl)-benzamide mp 155°-6°.