Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]([C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:16]=[C:15]([C:33]([NH2:35])=[O:34])[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][O:3]1.C(Cl)Cl.CO.Cl.O>O1CCOCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][N:8]([C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:33]([NH2:35])=[O:34])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC1(C)OCC(CN(c2cc(C(N)=O)nc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)S(C)(=O)=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N(CC(O)CO)c1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a suspension of 6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methyl sulfonamido)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (0.308 g, 0.596 g) in 85:15 DCM/MeOH (5 mL) was added 4M HCl in dioxane (1.0 mL). After 1 hour, water (0.5 mL) was added and a solid formed. After 1 hour, the solid was filtered and washed successively twice with 2 mL DCM, twice with 1 mL MeOH, once with 3 mL MeOH, and twice with 1 mL DCM. The solid was dried under vacuum at 40° C. to give 6-(N-(2,3-dihydroxypropyl)methylsulfonamido)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a white powder (0.200 g, 0.420 mmol, 70% yield). 1H NMR (400 MHz, DMSO-d6): 8.63-8.54 (3H, m), 8.01 (1H, s), 7.84 (1H, s), 7.33-7.26 (2H, m), 7.23-7.17 (2H, m), 7.09 (2H, d, J=8.8 Hz), 5.08 (1H, d, J=5.5 Hz), 4.80 (1H, t, J=5.7 Hz), 4.31-4.24 (1H, m), 4.05-3.96 (1H, m), 3.86-3.77 (1H, m), 3.54 (3H, s), 3.45-3.35 (2H, m). LC/MS: m/z=477.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](Cl)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1>C(Cl)Cl.O>[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([NH:1][C:2]4([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1
Reactant: COC(=O)CC1(N)CCOCC1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC1(NC(=O)c2ccc3c(ccn3Cc3cc(C)nc4c3CC=CC4)c2)CCOCC1
Yield: 17.2 %

Procedure:
The methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate (0.13 g, 0.75 mmol) from example (355) was combined with the acid chloride (0.20 g, 0.49 mmol) from step (402b) in methylene chloride (15 ml) and water saturated sodium bicarbonate (15 ml). The reaction was stirred for 3.5 hs, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (25:75, v:v) to give the methyl {4-[({1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]tetrahydro-2H-pyran-4-yl}acetate (0.04 g, 17%) as a solid, MS (M+H)+=472.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]=1I.CC1CCCO1.C([Mg]Cl)(C)C.O1CCCC1>O.C(O)(=O)C>[I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)c(I)n2CCN2CCCC2)CC1
Agent: CC(C)[Mg]Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Combine tert-butyl 4-[4,5-diiodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate (39 g, 64.97 mmol) and 2-methyltetrahydrofuran (273 mL), then cool to −15° C. Add 2 M isopropylmagnesium chloride in tetrahydrofuran (32.48 mL, 1.0 eq) dropwise over 45 minutes, maintaining the temperature below −10° C. Stir for an additional 30 min. Add acetic acid (7.45 mL) dropwise, then water (120 mL). Wash the aqueous phase with methyl tert-butyl ether (2×50 mL). Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo. Crystallize the resulting oil from hexanes/methyl tert-butyl ether to give tert-butyl 4-[4-iodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate as a white solid (29 g, 94%). MS (ES) m/z=475 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(O)C>C(Cl)Cl.O>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: O=C(Cl)C1CCCC1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.500 g, 1.59 mmol) in 20 mL of CH2Cl2 was placed under an atmosphere of nitrogen, treated with triethylamine (0.443 mL, 3.34 mmol) and then cooled to 0° C. with an ice water bath. The reaction mixture was treated with cyclopentanecarbonyl chloride (0.203 mL, 1.67 mmol) over 2 min. The reaction was stirred and allowed to come to ambient temperature over 2 h. After 18 h, the reaction was quenched with 15 mL of 10% Na2CO3 solution. The mixture was diluted with 25 mL CHCl3, mixed and then separated. The organic portion was washed with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan foam. The foam was purified by chromatography (SiO2, 96:4 CHCl3: methanol (MeOH)) to yield a light tan solid. The solid was dissolved in boiling 2-propanol (IPA), cooled to ambient temperature and then water was added until an off-white solid precipitated from solution. The precipitate was triturated in the IPA/H2O mixture for 2 h and then collected by vacuum filtration to give N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)cyclopentanecarboxamide (0.106 g) as an off-white solid. mp 75–77° C.;
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C:12]2(C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[CH3:38][CH2:39][O:40][C:41](C)=[O:42]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:13][CH2:14][N:15]([C:41]([O:40][CH2:39][C:38]4[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=4)=[O:42])[CH2:16][CH2:17]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(NCc1nccnc1Cl)C1(C(=O)OCc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Temperature: 25 °C

Procedure:
To a suspension of benzyl 4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-4-carboxylate (0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. was slowly added POCl3 (0.082 mL, 0.88 mmol). After stirring at rt for an hour the mixture was cooled to 0° C. then treated with solid NaHCO3. The mixture was stirred for 20 min at rt, diluted with water and extracted with EtOAc (3×20 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL), then dried over Na2SO4, and concentrated in vacuo to yield 2.07 g of desired product. 1H NMR (400 MHz CDCl3): δ 1.98-2.04 (m, 4H), 3.03-3.20 (m, 3H), 4.30-4.33 (m, 2H), 5.16 (s, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.35-7.38 (m, 5H), 7.26 (d, J=4.4 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 371.22 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5](I)=[N:4][C:3]=1[C:24]([O:26][CH3:27])=[O:25].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:7]=2)[C:2]([OH:1])=[C:3]([C:24]([O:26][CH3:27])=[O:25])[N:4]=1)#[N:29]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc4ccccc34)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 4-hydroxy-1-iodo-7-(naphthalen-1-yloxy)isoquinoline-3-carboxylate (130 mg, 0.28 mmol) and CuCN (49 mg, 0.55 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 87 mg. MS: (−) m/z 369.31 (M−1).
Reaction SMILES: Cl.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[NH2:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[C:32]([CH2:34][CH2:35][Cl:36])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:23][C@@H:22]1[OH:37].C1C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[CH2:52][C:53](Cl)=[O:54].C(Cl)(=O)C(Cl)=O>O.[OH-].[Na+].CO.C(O)C>[Cl:36][CH2:35][CH2:34][C:32]1[C:30](=[O:31])[NH:29][C:27](=[O:28])[N:26]([CH:33]=1)[C@@H:24]1[O:25][C@H:21]([CH2:20][NH:19][C:53](=[O:54])[CH2:52][C:46]2[C:45]([Cl:44])=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:51])[C@@H:22]([OH:37])[CH2:23]1
Reactant: NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=C(Cc1c(Cl)cccc1Cl)NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O

Procedure:
0.32 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine uridine hydrochloride were dissolved in a mixture of 5 ml of water and 2.5 ml of 1M sodium hydroxide solution. The mixture was shaken vigorously for 25 minutes with a benzene solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 0.22 g of the acid by treatment with oxalyl chloride). The resulting solid was removed by filtration and washed with water and then with diethyl ether to give 0.29 g of crude product of melting point 248°-249° C. (decomposition). 0.1 g of this solid was stirred successively for 1 hour each time with 1 ml of water, 2 ml of ethanol and 2 ml of methanol to give 0.03 g of 5-(2-chloroethyl)-5'-[2-(2,6-dichlorophenyl)-acetamido]-2',5'-dideoxyuridine of melting point 253°-254° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>ClCCl>[Cl:11][C:10]1[C:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])=[CH:3][C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC#CC(C)Oc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(Cl)cc1C(N)=O

Procedure:
0.75 g of (S)-N-(8-methyl-8-azabicyclo 3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide, 0.51 g of 2,2,2-trichloroethyl chlorocarbonate and 0.41 g of potassium carbonate were added to toluene. The obtained mixture was refluxed for 3 hours and cooled, followed by the addition thereto of dichloromethane. The resulting mixture was washed with 1N hydrochloric acid, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane (1:4) mixture) to give 0.50 g of (S)-N-(8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo 3.2.1!oct-3α-yl)-5-chloro-2-(1-methyl-2-butynyl)oxy-4-(2,2,2-trichloroethoxycarbonylamino)benzamide.
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CCO>[C:2]1([C:1]2[N:20]=[N:19][C:15]([OH:17])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1nnc(-c2ccccc2)c2cccnc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3-benzoylpicolinic acid (0.272 g, 0.120 mmol) and hydrazine hydrate (0.17 mL, 0.37 mmol) in EtOH (3.3 mL) was stirred at 80° C. overnight, concentrated, diluted with saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and concentrated to give the title compound as a white solid (0.28 g, 0.12 mmol). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.10 (dd, 1H), 8.09 (dd, 1H), 7.88 (dd, 1H), 7.54-7.63 (m, 5H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3nc(C)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3nc(C)cs3)cnc(CN)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
[6,7-Dimethoxy-4-(4-methyl-thiazol-2-ylamino)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (11.6 mg, 0.0269 mmol) in CH2Cl2 (0.6 mL) was added a 4.0 M HCl solution in dioxane (0.40 mL) at room temp. After the reaction mixture was stirred at room temperature for 5.0 h, the suspension was filtered. The yellow solid was further dried in vacuo to give (1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-(4-methyl-thiazol-2-yl)amine hydrochloride salt (7.4 mg; 75%). 1H-NMR (D2O): δ, 8.33 (s, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 6.34 (s, 1H), 4.70 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.05 (s, 3H); MS: calculated for C16H19N4O2S (M−Cl) 331.0; found: 331.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl.Cl[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[C:51]([F:53])[CH:52]=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:53][C:51]1[CH:52]=[C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:48]=[N:49][CH:50]=1
Reactant: Fc1cncc(CCl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2cncc(F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-5-fluoropyridine hydrochloride (Carlson et al., Acta Pharmaceutica Suecica, 1972, 9, 411-414) to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.45-8.38 (m, 2H), 7.37-7.34 (m, 1H), 7.24-7.14 (m, 2H), 7.04-7.00 (m, 1H), 6.78-6.75 (m, 1H), 6.46 (s, 1H), 6.17 (s, 1H), 5.03-4.85 (m, 3H), 4.64-4.61 (m, 1H), 4.16-4.04 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.3, 144.7, 144.6, 141.4, 138.4, 138.1, 137.8, 132.1, 129.0, 124.3, 123.9, 122.1, 121.9, 120.6, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 41.1; MS (ES+) m/z 405.0 (M+1).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][N:6]=1.O>CN(C=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:2]#[N:3])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1C#N
Temperature: 25 °C
Yield: 74 %

Procedure:
Copper(I) cyanide (21 g, 0.24 mol) was added to a solution of 2,5-dibromo-3-methylpyridine (49, 60 g, 0.24 mol) in dry DMF (200 mL), and the mixture was heated at reflux for 2 h. After cooling to room temperature, water (1500 mL) was added to the mixture and the products were extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (3×300 mL), brine (300 mL), dried with sodium sulfate and evaporated to dryness. The brown oily residue was subjected to flash column chromatography (silica gel), eluting with chloroform, to yield 50 as a white solid (35 g, 74%): mp 86-88° C. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=1.8 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.75, 140.68, 139.95, 132.25, 124.61, 115.90, 18.59; EIMS m/z 196/198 (M+); CIMS 197/199 (MH+). The 1H NMR spectrum is consistent with previously published data (Bioorg. Med. Chem. 1999, 7, 1845-1855).
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH2:18].[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH:18][C:5](=[O:6])[CH3:7]
Reactant: C[C@H]1Cc2ccccc2[C@H]1N
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N[C@@H]1c2ccccc2C[C@@H]1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of Ac2O (1.45 g, 14.2 mmole) in toluene (12 ml), was added dropwise a solution of (rac), (cis)-2-methyl-1-aminoindan (Ex. 39, 1.85 g, 12.6 mmole). The mixture was heated at 90° C. for 15 min, cooled to 70° C., and a solution of 1.1 g KOH in 8.3 ml water was added. The reaction mixture was stirred at ambient temperature for 2 hrs; the solid was collected by filtration, washed with toluene (10 ml), dried and crystallized from hexane:EtOAc, to give 1.85 g (9.8 mmole, 78%), mp: 146°-7° C.
Reaction SMILES: II.[C:3]([Si:7]([O:10][CH2:11][C:12]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[CH2:13])([CH3:9])[CH3:8])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].[OH:25]O.[OH-].[Na+]>C1COCC1.O>[Si:7]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)[CH2:13][OH:25])([C:3]([CH3:6])([CH3:4])[CH3:5])([CH3:9])[CH3:8]
Reactant: C=C(COc1ccc(I)cc1)CO[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A solution of iodine (282 mg, 1.11 mmol) in anhydrous THF (1.5 mL, then 2×0.75 mL to rinse) was added dropwise (over 40 min) to a stirred mixture of alkene 167 (1.71 g, 4.23 mmol) and powdered NaBH4 (90 mg, 2.38 mmol) in anhydrous THF (5.5 mL) at 0° C. under N2. After stirring at 0° C. for 4 h, and then at room temperature for 13 h, the mixture was again cooled to 0° C., treated with 30% H2O2 (2.4 mL) and 3N NaOH (2.4 mL), and then stirred at room temperature for 3 h. Water (50 mL) was then added, and the mixture was extracted with EtOAc (4×50 mL). The extracts were washed with brine (50 mL) and evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 4-5% EtOAc/petroleum ether gave 3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(4-iodophenoxy)methyl]-1-propanol (169) (1.26 g, 71%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.55 (dt, J=9.0, 2.7 Hz, 2H), 6.69 (dt, J=9.0, 2.7 Hz, 2H), 4.06 (dd, J=9.3, 6.7 Hz, 1H), 4.01 (dd, J=9.3, 5.9 Hz, 1H), 3.93-3.80 (m, 4H), 2.36 (dd, J=6.3, 5.1 Hz, 1H), 2.17 (sept, J=5.4 Hz, 1H), 0.89 (s, 9H), 0.06, 0.05 (2 s, 6H); HRFABMS calcd for C16H28IO3Si m/z [M+H]+ 423.0853. found 423.0849.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[N:18]=1)[C:5]([CH:7](C(OC)=O)C(OC)=O)=[O:6].O>CS(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([Cl:1])[N:18]=[C:17]([Cl:19])[CH:16]=1)(=[O:6])[CH3:7]
Reactant: COC(=O)C(C(=O)OC)C(=O)c1cc(Cl)nc(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1328 g (4.34 mol) of dimethyl 2,6-dichloro-isonicotinoyl-malonate are dissolved in a mixture of 3.45 l of dimethyl sulphoxide and 156.2 g (8.68 mol) of water. The reaction mixture is heated to 140° C. and stirred at this temperature for 30 minutes. After this, the reaction mixture is cooled to 10° C. and then added to 8.4 l of ice-water. The mixture is extracted twice with a total of 3.6 l of dichloromethane and the combined organic phases are washed once with 1.5 l of saturated, aqueous sodium hydrogen carbonate solution. After drying over sodium sulphate, the organic phase is concentrated under reduced pressure. The residue which remains is distilled under reduced pressure. In this manner 506.0 g (60% of theory) of 4-acetyl-2,6-dichloropyridine of boiling point 98° C. at 0.5 mbar are obtained. ##STR36##
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)=[O:8])C>CO.O1CCCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:17][CH2:18]2)=[N:20][CH:21]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Yield: 93.5 %

Procedure:
4N Aqueous solution of sodium hydroxide (5 ml) and water (5 ml) were added to a solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (1.0 g) described in Reference Example 81(2) in methanol (10 ml) and tetrahydrofuran (10 ml), and stirred at 80° C. for eight hours. After completion of the reaction, the organic solvent was evaporated and the aqueous layer was washed with diethyl ether. Concentrated hydrochloric acid was added to the aqueous layer under ice cooling, pH was adjusted to 4-5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid (864 mg) as a colorless solid.