Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 200 g of 4-nitro-3-(4-methoxyphenyl)-butanoic acid methyl ester, 68 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqeous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methoxyphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cc(CCl)ccc1C
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.125 g of 4-chloromethyl-2-(3-methoxypropoxy)-1-methylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rt=6.39.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40].C(N(CC)CC)C>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reactant: CN(C)C(=O)CCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(CC(=O)N(C)C)CC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C

Procedure:
A solution of Example 146C (0.047 g, 0.087 mmol), 2-chloro-N,N-dimethylacetamide (0.011 g, 0.091 mmol) and triethylamine (0.029 mL, 0.208 mmol) in 1-methyl-2-pyrrolidinone (0.8 mL) was heated to 75° C. for 1 hour. The reaction was cooled to ambient temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was taken directly to the next step without further purification. MS ESI(+) m/z 628.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl>[CH2:45]([O:44][C:42](=[O:43])[O:20][CH2:19][N:11]1[C:12](=[O:18])[C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]([O:8][C:7]2[C:6]([Cl:21])=[CH:5][C:4]([N:22]3[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]3)=[CH:3][C:2]=2[Cl:1])=[N:10]1)[CH3:46]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), 4-N,N-dimethyaminopyridine (25.3 mg, 0.21 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol), in methylene chloride (3 mL) at 0° C. was treated with ethyl chloroformate (45 μL, 0.47 mmol). The reaction was stirred at allowed to gradually warm to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 1-10% methanol/methylene chloride) followed by reverse phase chromatography (Pursuit C-18 column, acetonitrile gradient with ammonium acetate) afforded carbonic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester ethyl ester (89.9 mg, 39%) as a white solid. ES+-HRMS m/e calcd for C21H18N6O7Cl2 (M+H+) 537.0687, found 537.0686.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][C:25]([OH:24])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:27]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.112 g) in methanol (5 mL) was treated with 4-hydroxy-4-phenylpiperidine (0.057 g) and the pH was adjusted to 6 by adding acetic acid. After treating with sodium cyanoborohydride (0.030 g), the reaction mixture was stirred at ambient temperature for 16 hours, diluted with a saturated solution of sodium bicarbonate, and extracted with dichloromethane. The organic layers were dried and evaporated to obtain 3-[1-(3,4-dichlorophenyl)-3-(4-hydroxy-4-phenylpiperidino)propyl]-2-methyl-2,3-dihydroiso-indol-1-one as a foam (0.104 g). This material was transformed into the hydrochloride salt as follows. The above product was dissolved in dry dichloromethane (2 mL) and treated with HCl in ether (2 mL). The resulting solution was diluted with anhydrous ether, stirred for 2 hours and the resulting precipitate was collected to afford the title compound (0.075 g); mp 160° C. (dec); MS: m/z=509(M+1); NMR: 1.79 (broad,2), 3.32 (s,3), 3.75 (broad,1), 4.88 (m,1), 5.44 (s,1), 6.80-7.95 (m,12). Analysis for C29H30Cl2N2O2.HCl. 0.5 H2O: Calculated: C, 62.76; H, 5.81; N, 5.13; Found: C, 62.79; H, 5.89; N, 4.89.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].C(O)C>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g 10% [w/w]) was added to a 1L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in ethanol (200 mL) and transferred to the hydrogenation flask. Concentrated aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241° C.).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCBr)cc12
Reactant: Sc1ccccn1
Product: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12

Procedure:
Prepared analogous to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril (m.p. 217°-219° C.) and 2-mercapto-pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[C:25]1([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:23]([C:20]1[N:19]=[C:18]([C:14]2[N:15]=[CH:16][C:17]3[N:5]([CH2:4][CH2:3][CH2:2][N:34]4[CH2:33][CH2:32][C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)([OH:37])[CH2:36][CH2:35]4)[C:6]4[C:11]([C:12]=3[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[O:22][N:21]=1)[CH3:24]
Reactant: CCc1noc(-c2cc3c4ccccc4n(CCCCl)c3cn2)n1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c4ccccc4n(CCCN4CCC(O)(c5ccccc5)CC4)c3cn2)n1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
To a solution of Compound 3 (1.0 g, 3 mmol) in anhydrous DMF (50 mL), 4-phenylpiperidin-4-ol (0.63 g, 3.5 mmol) and TEA (1 mL) were added. The resulting mixture was heated at 85° C. for 76 h under a nitrogen atmosphere. The solvent was removed in vacuo, and the solid residue was submitted to column chromatography on silica gel with CH2Cl2 /methanol (9:1) as eluent. The purified compound was precipitated as the hydrochloride, giving the title compound (0.6 g, 36%) as an yellow solid. M.p. 169°-170° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (1.43 g), 4-(4-chloromethylphenoxy)methyl-2-phenyloxazole (1.88 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (2.81 g, yield: 92%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 114˜115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[C:12]([CH2:14][C:15]([O:17]CC)=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Yield: 81.2 %

Procedure:
7.0 g of ethyl 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 2.0 g of potassium hydroxide are treated in the same manner as described in Example 16. 5.25 g of 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 81.0%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][C:20]=1[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:26]([O:25][C:23]([C:22]1[CH:30]=[CH:31][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[C:20]([CH3:32])[CH:21]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1O
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3C)c(C#N)cc21
Temperature: 150 °C
Yield: 37 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (0.200 g, 0.850 mmol), tert-butyl 4-hydroxy-3-methylbenzoate (0.195 g, 0.935 mmol) and potassium carbonate (0.141 g, 1.02 mmol) were dissolved in 4 mL of dry DMSO and degassed with argon. The solution was heated in a microwave oven at 150° C. for 15 minutes, then at 170° C. for 15 additional minutes. The reaction was poured into 10% HCl/water (1 L), extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow film. The crude product was adsorbed onto silica gel and purified by column using 20-30% ethyl acetate/hexanes to provide the desired product (0.133 g, 37%) as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NCC(O)c2cc(Cl)sc21
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution 6-chloro-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-4-ol 1,1-dioxide (9.0 g, 37.6 mmol) in dimethylformamide (200 mL, anhydrous) and sodium hydride (60% in oil, 1.66 g, 41.5 mmol) was reacted with 1,4-dibromobutane at 0°. The reaction was stirred in an ice bath for 30 min and then it was allowed to warm to room temperature and stir for three days. The mixture was poured into ice water (400 mL) and extracted with diethyl ether (2×200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and then were dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel flash chromatography with hexane/ethyl acetate (7:3) to give 6-chloro-3,4-dihydro-2-(4-bromobutyl)-2H-thieno[3,2-e]-1,2-thiazine-4-ol 1,1-dioxide as a colorless oil (10.62 g, 75%); the 1H NMR was consistent with the structure.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6]([O:11][CH3:12])=[N:7][CH:8]=[N:9][CH:10]=1.O.[OH-].[Li+]>O.C(O)C>[CH3:12][O:11][C:6]1[C:5]([CH2:4][C:3]([OH:13])=[O:2])=[CH:10][N:9]=[CH:8][N:7]=1
Reactant: COC(=O)Cc1cncnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ncncc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.21 g (1.14 mmol) of methyl(4-methoxy-5-pyrimidinyl)acetate from Step A in 0.5 mL of water and 1.5 mL of ethanol was added 81 mg (1.9 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 3 mL of 2.0 N aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound as an off white solid (191 mg, 90%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 4.01 (s, 3H), 3.57 (s,2H). LC-MS: m/z (E/S) 169 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[OH-].[K+]>O>[CH:4]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Add 20.0 g (0.10 mole) γ-chloro-p-fluorobutyrophenone dropwise to a methanolic KOH solution (prepared from 9.8 g of 86% KOH pellets and 60 ml of methanol). Stir the mixture at room temperature for 40 minutes and pour into 100 ml of water and then extract with 3×30 ml of methylene chloride. Wash the methylene chloride extracts with 3×40 ml of water, dry over magnesium sulfate and evaporate off the solvent to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:24][N:25]=[C:26]=[S:27].O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@:7]2([C:26](=[S:27])[NH:25][CH3:24])[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: O=[S@@]1CCCC[C@@H]1c1cccnc1
Reactant: CN=C=S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[S@]1=O
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A stirred suspension of (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (50.0 g) in dry tetrahydrofuran (500 ml) is treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (281 ml;1M) at between -5° C. and +5° C. The resulting suspension is stirred for 15 minutes at between -5° C. and +50C. and then it is treated with a solution of methyl isothiocyanate (20.26 g) in dry tetrahydrofuran (63 ml) at between -5° C. and +50C. The mixture is stirred at between -5° C. and +5° C. for 30 minutes and then it is treated with water (500 ml). The aqueous phase is then washed with dichloromethane (2×150 ml), The aqueous solution is then treated with charcoal, filtered, neutralised by treatment with dilute hydrochloric acid (2N) and filtered, to give (1R,2R)-2-(3-pyridyl)-N-methyltetrahydro-2H-thiopyran-2-carbothioamide 1-oxide (50.64 g), in the form of a white powder, m.p. 215°-216° C., enantiomeric excess greater than 99.6%. [NMR (CDCl3):- 1.6(m,1H), 1.7(m,2H),2.2(m, 1H),2.3(m, 1H),2.9(m,1H), 3.0(m,1H),3.1 (d,3H),3.7(m,1H),7.3(m,1H), 8.1 (m,1H),8.3(m,1H),8.5(m,1H),8.7(m,1H)]; specific rotations (sodium D line) -205° (c=1, 28° C., CHCl3); -281° (c=1, 31° C., EtOH).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1.Cl>CN(C)C=O.O>[CH2:11]([C:5]([CH2:13][CH3:14])([CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:4][O:3][C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:12]
Reactant: CCC(CC)(CO)CS(N)(=O)=O
Reactant: Cc1cc2ncnn2nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(COc1nn2ncnc2cc1C)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
In 20 ml of dimethylformamide was suspended 0.672 g of 60% sodium hydride in oil, followed by addition of 1.72 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 1 hour. To this was added 1.35 g of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. Following addition of 70 ml of iced water, the reaction mixture was adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3 portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-ethyl acetate-methanol (10:10:1). The fractions containing the object product were pooled and concentrated, and 50 ml of 5N-hydrochloric acid was added to the residue. The mixture was refluxed for 30 minutes. After cooling, the mixture was concentrated under reduced pressure and the residue was diluted with water and aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate-tetrahydrofuran (1:1). The extract was washed with saturated aqueous solution of sodium chloride once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hot ethanol to provide 0.79 g of the title compound. m.p. 189°-192° C.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:ethanol (60:40 v/v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:ethanol (60:40 v/v, 106 ml) at room temperature. The reaction mixture was stirred at room temperature for an additional 16 hours to obtain a pH of 4.11. The white solid was filtered, washed with ethanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Reactant: CC(C)C(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate (Example 89b) and isobutyric acid as brown solid (46%). MS 400 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Clc1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 227.9 (M+H)+.