Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:7]=1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1.O>[CH2:18]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a stirred solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole) in acetic acid (20 mL) was added hydroxylamine hydrochloride (0.878 g, 0.0126 mole) and the resulting mixture was heated to reflux for 3 hours. Volatiles were removed and the resulting residue was diluted with water, basified with sodium bicarbonate solution and extracted with ethyl acetate, washed the ethyl acetate with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.42 g (92%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester. LCMS: 324.12 (M+1)+, 78.58%. To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester (1.75 g, 0.00542 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (15 mL) was added NaOH (0.651 g, 0.01628 mol) and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with cold water. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 1.57 g (98%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid. LCMS: 296.08 (M+1)+, 84.73%
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:16])[C:14]#[CH:15])[CH2:9]1)=O)(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:50][C:51]1[C:56]([Cl:57])=[CH:55][CH:54]=[C:53]([Cl:58])[C:52]=1O.C1(O)C=CC=CC=1.Cl.CCO>C1(C)C=CC=CC=1>[Cl:50][C:51]1[C:56]([Cl:57])=[CH:55][CH:54]=[C:53]([Cl:58])[C:52]=1[O:16][CH:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]#[CH:15]
Reactant: Oc1c(Cl)ccc(Cl)c1Cl
Reactant: C#CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: Oc1ccccc1
Product: C#CC(Oc1c(Cl)ccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-3-(1-hydroxyprop-2-ynyl)pyrrolidine-1-carboxylic acid t-butyl ester (21.0 mg, 93.2 μmmol) and DIAD (22.0 μL, 112 μmmol) was dissolved in toluene (65 μL, 610 μmmol) at room temperature. PPh3 (29.3 mg, 112 μmmol) and 2,3,6-trichlorophenol (20.2 mg, 102 μmmol) were dissolved in toluene (0.1 mL, 1 mmol) and heated at 100° C. The t-butyl ester mixture was slowly added into the phenol mixture at 100° C., and stirred for 1 hour. The mixture was then removed from the heat and stirred at room temperature overnight. The mixture was then concentrated and the resulting residue was treated with 1.25M HCl in EtOH (0.6 mL, 0.8 mmol) at room temperature overnight. The mixture was concentrated and the residue was redissolved in a mixture of 50% AcOH/H2O (1.4 mL) and MeCN (0.2 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (21.2 mg, 99% purity). MS m/z: [M+H]+ calcd for C13H12Cl3NO, 304.00; found 304.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:18][C:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[CH:29]([Si:32](Cl)([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:5]=[C:4]([C:14]2[NH:18][C:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH:15]=2)[CH:3]=[C:2]([O:1][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Benzyl 5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (27.35 g, 71.7 mmol) synthesized in Example (106a) was dissolved in methylene chloride (350 mL), and triisopropylsilyl chloride (18.4 mL, 86.0 mmol), triethylamine (30.0 mL, 215 mmol) and 4-dimethylaminopyridine (10.53 g, 86.2 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (400 mL) was added to separate the solution, and the organic layer was washed with saturated brine, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=3%-20%) to afford the desired product (34.41 g, yield 89%) as a pale yellow oil.
Reaction SMILES: ClC(OCCCl)=O.[N:8]1([C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[CH2:30]([NH2:33])[C:31]#[CH:32]>C(Cl)(Cl)Cl>[CH2:30]([NH:33][CH2:20][CH2:17][O:16][C:14]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:15])[C:31]#[CH:32]
Reactant: C#CCN
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(Cl)OCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNCCOC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-chloroethyl chloroformate (429 mg, 3 mmol) was added slowly to a mixture of tert-butyl 1-piperazinecarboxylate obtained as step (ii) in Example 2 (559 mg, 3 mmol) and diisopropylethylamine (407 mg, 3.15 mmol) in CHCl3 (25 ml) at 0° C. The mixture was stirred for 2 h at room temperature. CHCl3 (50 ml) was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was dissolved in CH2Cl2 (25 ml) at room temperature, and propargylamine (0.205 ml, 165 mg, 3 mmol) was added. After 24 h of stirring at room temperature, the solvent was removed by vacuum, and to the residue was added 20 ml of a solution of TFA:H2O:TES:thioanisole (85:5:5:5). The mixture was then stirred at room temperature for 2 h. The solution was evaporated to dryness in vacuum. The resulted residue was dissolved in water (10 ml) and then basified with Na2CO3 (pH 11), and extracted with Et2OAc (3×50 ml). The organic layer was washed with brine (2×50 ml) and dried over Na2SO4 overnight. Evaporation in vacuum gave the title compound H1: (251 mg, 40% total yield). H1 NMR (250 MHz, CDCl3+D2O) 2.26 (m, 1H), 3.11 (s 2H), 3.29 (dd, J=10.21, 7.45 Hz, 2H), 4.29 (d, J=11.23, 7.12 Hz, 2H), 2.55 (dd, J=4.73, 4.50 Hz, 4H), 2.93 (dd, J=4.96, 4.84 Hz, 4H). Mass spectrometry: calculated for C10HnN3O2 m/z [M+H]+=212.26. found [M+H]+=212.22.
Reaction SMILES: [S:1]1[C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[NH:14]1[CH2:18][CH2:17][NH:16][C:15]1=[S:19].C(O)C>C(O)(=O)C>[BrH:8].[S:1]1[C:5]([C:6]2[N:16]3[CH2:17][CH2:18][N:14]=[C:15]3[S:19][CH:7]=2)=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: S=C1NCCN1
Reactant: O=C(CBr)c1cc2ccccc2s1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: C1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 1-(benzo[b]thiophen-2-yl)-2-bromoethan-1-one (21.96 g), 2-imidazolidinethione (7.81 g) and ethanol (300 ml) was heated under reflux for 10 minutes. Acetic acid (150 ml) was added, then the mixture was heated under reflux for 18 hours and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethanol (50 ml) and ether (50 ml), then dried in vacuo at 100° C. for 3 hours to give 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (19.6 g) as a light brown solid, m.p. 275-285° C. (decomposes).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:15]Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:15][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
3,5-Bis(t-butyl)-1-(bromomethyl)benzene (170 mg, 0.60 mmol), t-butyl piperazine carboxylate (102 mg, 0.55 mmol) and potassium carbonate (151 mg, 1.10 mmol) were dissolved in a solvent mixture of acetone (2 ml) and DMF (0.2 ml), and the mixture was stirred overnight while heated under reflux. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and then the filtrate was evaporated under reduced pressure. The concentrate was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 120 mg (yield: 56%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][N:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Brc1ccc(OCCN2CCCC2)cn1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cn3)nc2)cc1

Procedure:
Prepared according to general working method I from 2-bromo-5-(2-pyrrolidin-1-yl-ethoxy)-pyridine (271 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
4.0 g (16.59 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) of HATU, 10.41 ml (59.74 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 l of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.0 g (85% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C1COCC1.[NH:25]([CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[NH2:26]>CO>[ClH:1].[N+:17]([C:5]1[CH:4]=[CH:3][C:2]2[N:25]([CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[N:26]=[C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[O:7][C:6]=1[C:15]=23)([O-:19])=[O:18]
Reactant: O=c1c2ccccc2oc2c([N+](=O)[O-])ccc(Cl)c12
Reactant: NNCCNCCO
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: O=[N+]([O-])c1ccc2c3c(nn2CCNCCO)-c2ccccc2Oc13
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 2.76 g of 1-chloro-4-nitro-9H-xanthen-9-one, 30 ml of THF, 15 ml of methanol and 1.40 g of 2-[(hydrazinoethyl)amino]-ethanol was stirred at room temperature for three days. The precipitate was collected, washed with THF and dried, providing the title compound, mp 262°-64° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:21]([CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH3:20].C(OC)(OC)OC.[BH4-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN(CCC)CCCCN
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: O
Product: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
The compound (225.3 mg) obtained in Example 103-3 was dissolved in methanol (6.76 ml). Then, the solution was added with the compound (165.0 mg) obtained in Example 1-2 and trimethyl orthoformate (304.8 mg), followed by stirring at room temperature for 18 hours. Sodium borohydride (108.7 mg) was added to the solution under ice-cooling, followed by stirring at room temperature for 0.5 hours. The reaction solution was added with water and subjected to separation/extraction with chloroform. Then, the extract was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (297.6 mg) as a colorless oily substance.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH2:16][C:17]1[NH:18][CH2:19][CH2:20][N:21]=1.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.C(OCC)C>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:1]([N:21]2[CH2:20][CH2:19][N:18]=[C:17]2[CH2:16][O:15][C:14]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:13]=2[CH3:12])=[O:2])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cccc(OCC2=NCCN2C(=O)Nc2ccc(Br)cc2)c1C
Reaction time: 2 h

Procedure:
A 17% solution of phosgene in toluene (3.2 g containing 0.5521 g; 0.00549 moles COCl2) in dry chloroform (15 ml) was added slowly with stirring at 0° C. to a solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (2.40 g, 0.0115 moles) in dry chloroform (20 ml). When addition was complete the reaction mixture was left at ambient temperature for 2 hours, diluted with an equal volume of dry diethylether and rapidly filtered. The filtrate, which contained the N-chlorocarbamoyl adduct of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline, was treated with freshly distilled dry 4-bromoaniline (1.22 g, 0.00714 moles) and the mixture left at ambient temperature overnight at which time tlc showed that the major compound was the desired product. The mixture was evaporated to dryness in vacuo and the residue taken up in a mixture of aqueous sodium carbonate and dichloromethane. The organic layer was washed with water, dried over magnesium sulphate and evaporated to dryness to give a residue which was purified as described in (A) above to give 1-(N-(4-bromophenyl)carbamoyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, identical with that obtained in (A) above.
Reaction SMILES: COC1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)C=1.C([S-])C.[Na+].[C:21]([O:24][C:25](=[O:27])[CH3:26])(=O)[CH3:22].P([O-])([O-])([O-])=O>CN(C=O)C>[C:25]([O:24][C:21]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:22]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2ncc3c(c2c1)CCCC3
Agent: CC[S-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncc3c(c2c1)CCCC3
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A mixture of 2-methoxy-7,8,9,10-tetrahydrophenanthridine (Compound 273, 48.17 g, 226 mmol) and sodium ethanethiolate (43.69 g, 520 mmol) in dry DMF was heated at 160° C. for 4 hours. After the reaction mixture was cooled to zero degrees C., acetic anhydride (63.9 mL, 678 mmol) was added and the reaction mixture was stirred for 30 minutes. The resulting thick white slurry was poured into 0.1 M pH 7.5 phosphate buffer (1.6 L) and extracted with ether (3×400 mL). The combined organic layers were washed with water (3×300 mL) and brine (300 mL), dried (MgSO4), filtered through a 3 cm×3 cm plug of silica, and evaporated in vacuo. The residue was purified by recrystallization from ethyl acetate-hexanes to give 45.70 g (86 percent) of Compound 274: white crystalline solid; mp 118°-119° C.; Rf =-- 0.39 (silica, 50 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 3018, 2938, 2861, 1758, 1507, 1369, 1193, 1174 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1 H, H6), 8,06 (d, J=9.0 Hz, 1 H, H4), 7.61 (d, J=2.5 Hz, 1 H, H1), 7.36 (dd, J=9.0, 2.5 Hz, 1 H, H3), 3.03 (t, J=6.0 Hz, 2 H, H7 or H10), 2.89 (t, J=6.0 Hz, 2 H, H7 or H10), 2.37 (s, 3 H, OCOCH3), 1.98-1.86 (m, 4 H, H8 and H9); 13C NMR (125 Mz, CDCl3) δ 169.5, 152.3, 148.4, 144.3, 140.9, 131.3, 130.1, 128,,0, , 122.9, 113.8, 27.0, 24.8, 22.2, 22.1, 21.1; MS (FAB+, m/e (rel intensity) 242 (M+H, 100), 200 (25); HR MS for C15H16NO2 (M+H), calcd 242.1181, found 242,1181. Anal. Calcd for C15H15NO2 : C, 74.67; H, 6.27; N, 5.80. Found: C, 74.66; H, 6.37; N, 5.64.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].I[CH2:22][CH2:23][CH2:24][CH2:25]I>CN(C)C1C=CN=CC=1.O>[N:6]1([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: ICCCCI
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
Anhydrous DMF (3 ml) was added to a flask charged with dimethyl 5-aminoisophthalate (0.250 g, 1.2 mmol, 1 eq) and 4-dimethylaminopyridine (0.308 g, 2.52 mmol, 2.1 eq) under Ar. 1,4-diiodobutane (0.16 ml, 0.37 g, 1.20 mmol, 1 eq) was added with stirring and the solution was heated to 90° C. After heating overnight the reaction was not complete. More diiodide (0.25 ml, 1.9 mmol, 1.6 eq) was added and the reaction was heated to 100° C. After heating overnight the reaction was cooled to room temperature and poured in water. The mixture was extracted with EtOAc (×2). The combined organic extracts were washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. The residue was stirred in CH2Cl2 and filtered through cotton to remove any insoluble material. The solvent was removed in vacuo. Purification via flash chromatography yielded the crude product. The crude was triturated with hexanes and the solid was collected via filtration. 0.167 g (0.63 mmol, 53% yield) of the product was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[BH-](O[C:28]([CH3:30])=O)(OC(C)=O)OC(C)=O.[Na+].Cl[CH2:33][CH2:34]Cl>>[C@H:34]12[CH2:33][C@H:7]([CH:2]=[CH:3]1)[CH2:6][C@@H:28]2[CH2:30][N:11]1[CH2:10][CH2:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])([O:14][CH3:15])[CH2:13][CH2:12]1
Reactant: COc1ccc(Cl)cc1C1(OC)CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Agent: [Na+]
Product: COc1ccc(Cl)cc1C1(OC)CCN(C[C@H]2C[C@H]3C=C[C@@H]2C3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(5-Chloro-2-methoxyphenyl)-4-methoxypiperidine 5d (51 mg, 0.2 mmol) was dissolved in 1,2-dichloroethane (1.5 mL) and treated with (S,S,S)-norbornene carboxaldehyde (24 mg, 0.2 mmol, 1.0 eq), followed by the addition of NaBH(OAc)3 (65 mg, 0.3 mmol, 1.5 eq). The reaction was allowed to stir at room temperature for 1 h, quenched with methanol (1 mL) and allowed to stir for another 30 min (until gas evolution stopped). The crude reaction mixture was purified by HPLC (10-99 CH3CN gradient, 0.05% TFA) to provide the desired product 1-(((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)methyl)-4-(5-chloro-2-methoxyphenyl)-4-methoxypiperidine (compound no. 140) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 362.2 [M+H]+, retention time 2.53 min.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][N:4]=1)=[O:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:11]=3[C:3]([CH:1]=[O:2])=[N:4]2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c(C=O)nn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
A mixture of methyl 3-formyl-1H-indazole-4-carboxylate (B1) (3.3 g, 16.1 mmol), 4-fluorophenylboronic acid (4.5 g, 32.3 mmol) and copper(II) acetate (3.99 g, 21.9 mmol) was degassed under nitrogen (3×). Anhydrous dichloromethane (240 ml) and triethylamine (4.5 ml, 13.5 mmol) were added. The mixture was degassed under nitrogen (2×) and stirred at ambient temperature for 21 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 9%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.91-7.88 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.69 (dd, J=8.4, 7.3 Hz, 1H), 7.53 (t, J=8.7 Hz, 2H), 3.93 (s, 3H); MS (ESI+) m/z 299 (M+H).
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][N:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][N:29]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3ccccc3)cn2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5RS)-2-oxo-5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (1.00 g, 1.78 mmol) in methanol (12 ml) was added a solution (4.3 ml, 2.13 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give-the objective substance (0.81 g, 85%).