Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D3 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:15]([NH2:17])=[O:16])=[N:13][NH:14][C:5]=3[C:4]=2[N:3]=1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:15]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([I:1])=[N:3][C:4]=3[C:5]=2[N:14]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]2)[N:13]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)c1n[nH]c2c1CCc1cnc(I)nc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(I)ncc2CC3)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (prepared following the method reported in WO2008074788A1) 50 mg, (0.146 mmol) in DMF (3 ml), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate 61 mg, (0.219 mmol) and Cs2CO3 95 mg, (0.293 mmol), were added. The mixture was heated at 70° C. and stirred for 4 hours. The cooled mixture was treated with water (10 ml) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography eluting with DCM/EtOH 9/1 to afford the desired title product 63 mg (80%) as a white solid. LC/MS (254 nm) HPLC method 2 Rt 6.51 min. 1H NMR (401 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 4.50-4.55 (m, 2H), 3.84-3.96 (m, 2H), 2.99-3.07 (m, 2H), 2.84-2.95 (m, 2H), 2.59-2.75 (m, 2H), 2.07 (s, 1H), 1.56 (br. s., 2H), 1.39 (s, 9H), 1.08-1.22 (m, 2H). HRMS (ESI) calcd for C21H27IN6O3 [M+H]+ 539.1262 found 539.1274.
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.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH3:34])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH3:34])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: CCOc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 59.2 %

Procedure:
Beginning with 0.139 gm (0.70 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.200 gm (0.70 mMol) 4-hydroxy-4-(6-ethoxynaphth-2-yl)piperidine, 0.191 gm (56%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CCOc1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(OCC)cc2)[nH]c1=O
Reaction time: 17 h
Yield: 70.6 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 4-ethoxyaniline (14.3 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g). M.p. 263°-265° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)C(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(C)C(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and isobutyryl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:38]#[N:39].CO>CN(C=O)C>[C:38]([NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1)#[N:39]
Reactant: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-({1-[4-(6-amino-pyridin-2-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (120 mg, 0.25 mmol) in DMF (2 mL) was treated with NaH (95%, 10 mg, 0.40 mmol) at 0° C. The reaction was stirred for 20 min. and BrCN (Aldrich, 32 mg, 0.30 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜0.2 mL) was added to quenched extra NaH. The reaction solution was partitioned between DCM and water. The aqueous layer was extracted with a chloroform/IPA “cocktail” (3:1 v/v). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([CH3:24])[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]1([C:31]2[O:32][C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][C:35](=O)[CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([CH:24]=[C:35]3[CH:36]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:32][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:34]3)[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1cc(-c2ccccc2)oc(-c2ccccc2)c1
Reactant: Cc1cc(-c2ccccc2)cc(-c2ccccc2)[o+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: C(=C1C=C(c2ccccc2)OC(c2ccccc2)=C1)c1cc(-c2ccccc2)cc(-c2ccccc2)[o+]1

Procedure:
A mixture of 3.5 g. of 2,4-diphenyl-6-methylpyrylium perchlorate, 2.5 g. of 2,6-diphenyl-4-pyrone and 40 ml. of acetic anhydride is refluxed for 15 minutes, cooled, and the solid is collected, washed with ether, and recrystallized from acetic anhydride. A product having a m.p. of 258° C. is obtained. The theoretical values for C35H25ClO6 and the actual values are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:27]([C:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:34]([C:31]3([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:33][CH2:32]3)=[O:35])=[CH:9][C:8]=2[C:14]([F:15])([F:16])[F:17])=[CH:18][CH:19]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Reactant: CCCCC1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC1(C(=O)Nc2ccc(Oc3ccc(Cl)cc3)c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 80.1 %

Procedure:
To a solution containing 2.9 g (0.01 mole) of the amine prepared in Example 4 (b), and 1.0 g (0.01 mole) of triethylamine in 50 ml of tetrahydrofuran was added dropwise 1.7 g (0.01 mole) of 1-butylcyclopropanecarboxylic acid chloride. The mixture was stirred and heated at 60° C. for 0.5 hour, poured into ice water and extracted with ether. The ether extract was dried and concentrated under reduced pressure. The residual yellow syrup was crystallized from hexane to give 3.3 g (80%) of product as a tan solid, m.p. 104°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:50]=[CH:49][C:16]([C:17]([N:19]([CH2:45][C:46]([OH:48])=O)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:51]([F:54])([F:53])[F:52])[CH:4]=1.[NH2:55][C:56]([CH3:62])([CH3:61])[C:57]([O:59][CH3:60])=[O:58].C1C=CC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:50]=[CH:49][C:16]([C:17]([N:19]([CH2:45][C:46]([NH:55][C:56]([CH3:62])([CH3:61])[C:57]([O:59][CH3:60])=[O:58])=[O:48])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:33]=[CH:34][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:36][CH:37]=5)[O:29][N:28]=4)=[CH:25][CH:26]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:51]([F:53])([F:52])[F:54])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 354 (15 mg, 0.02 mmol), methyl 2-amino-2-methylpropanoate (3.6 mg, 0.03 mmol) and HOBt (3.03 mg, 0.02 mmol) in anhydrous DMF (0.5 mL) was added dicyclohexyl carbodiimide (DCC) (4.6 mg, 0.02 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and allowed stir at room temperature for 36 h. The reaction was quenched with saturated NaHCO3 (2 mL) then extracted with EA (2×3 mL). The combined organic extract was washed with brine (5 mL), dried (MgSO4), filtered and concentrated to afford methyl 2-(2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetamido)-2-methylpropanoate INT-72 which was used in the next step without purification. LCMS-ESI (m/z) calculated for C46H42F3N5O7: 834; no ion observed, tR=4.44 min (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[OH-].[K+].[I:14]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[I:14]
Reactant: II
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cc2[nH]cc(I)c2cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.9 %

Procedure:
To a mixture of 5,6-difluoro-1H-indole (500 mg; 3.27 mmol) and KOH (458 mg; 8.18 mmol) in DMF (6.2 mL) was added a solution of iodine (837.5 mg; 3.3 mmol) in DMF (6.3 mL). The mixture was stirred at r.t. for 12 hours. It was poured into an ice-water mixture (60 mL) and extracted with EtOAc (20 mL×3). The combined organic layers was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered, concentrated to afford 930 mg (100%) of the title compound as a red solid. It was used to next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([NH2:20])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]#[N:20])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(N)=O)cc1CCS(=O)(=O)CCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCn1nc(C#N)cc1CCS(=O)(=O)CCC
Temperature: 25 °C
Yield: 101 %

Procedure:
1-Butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide (4.00 g, 13.27 mmol) in toluene (66 mL) was treated with phosphorous oxychloride (2.50 mL, 26.5 mmol). The solution was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting oil was diluted with water (50 mL) and saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3]1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:31]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Product: COC(=O)[C@H](CCC(=O)c1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized (420 mg, 6%) following a similar procedure as set out earlier in Description 2 starting from 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 3.69 g, 15.2 mmol) and 3-bromophenyl phenylmethyl ether (D39); Rt (HPLC): 6.2 min.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]([CH2:24][NH2:25])[CH2:22][OH:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:33]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[O:33]([C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:25][CH2:24][C@H:21]([NH:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][OH:23])(=[O:48])=[O:47])=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-triphenylmethylamino-3-aminopropanol (1.99 g, 6 mmol) in CH2Cl2 (12 mL) at 0° C., triethylamine (1.7 mL, 12 mmol) was added dropwise followed by the addition of 4-phenoxybenzenesulfonyl chloride (1.61 g in 12 mL CH2Cl2). The reaction mixture was stirred at RT for 2 h and then was washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated and purified through column chromatography (silica gel, 35% EtoAc in pet. ether) to afford (S)-3-(4-phenoxybenzenesulfonamido)-2-(tritylamino)propanol as colorless solid in 74% (2.52 g) yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[CH2:5]([N:4]([CH2:3][CH2:2][NH:1][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCN(Cc1ccccc1)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCN(Cc3ccccc3)c3ccccn3)[nH]c2=O)cn1

Procedure:
2-[N-(2-aminoethyl)-N-benzylamino]pyridine (0.95 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.91 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with ether and recrystallised from methanol to give 2-[2-(N-benzyl-N-pyrid-2-ylamino)ethylamino]-5-(6methylpyrid-3-ylmethyl) pyrimid-4-one, 1.02 g (68%) mp 178°-82° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11]>>[C:4]([O:11][CH2:10][CH:9]([O:8][CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: COC(CO)c1ccccc1
Product: COC(COC(=O)CC(C)=O)c1ccccc1

Procedure:
In a similar manner, diketene was reacted with (±)-2-methoxy-2-phenylethanol to obtain 2-methoxy-2-phenylethyl acetoacetate, BP 115°-120° C./0.2 mm.
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([OH:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].O.[Na].[OH-].[Na+:18].C(CN)CC(P(O)(O)=O)(P(O)(O)=O)O>O.C(O)C>[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([O-:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[Na+:18]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Reaction time: 15 h

Procedure:
In accordance with the aspects of this invention wherein alendronic acid monohydrate is converted to,alendronate sodium, alendronic acid monohydrate as prepared by any of the known methods is added to an alkanol, preferably ethanol, together with a sodium base, preferably sodium hydroxide, and a desired amount of water. The amount of water depends upon the crystal form that is desired. The molar ratio of sodium base to alendronic acid is 1:1. The reaction mixture is boiled under reflux while stirring vigorously for approximately 15 hours, until the pH of the liquid phase remains constant (approx. pH 7). Crystalline alendronate sodium is then isolated, preferably by filtration after cooling to ambient temperature followed by washing with absolute ethanol, washing with absolute ether and drying overnight in a vacuum oven at ambient temperature and at a pressure of 10 mm to 15 mm of mercury.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:23].Cl>O1CCOCC1>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:31])=[CH:26][CH:25]=1)=[O:23]
Reactant: CCCCO
Reactant: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 5 h
Yield: 80.5 %

Procedure:
On the other hand, 0.8 g of n-butanol and 2.0 g of triethylamine were dissolved in 20 ml of dioxane. To this solution, a solution prepared by dissolving above 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride in 5 ml of dioxane, was dropwise added over a period of 5 minutes at room temperature under stirring. After completion of the dropwise addition, the stirring was continued at room temperature for further 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of a 2% hydrochloric acid aqueous solution. The precipitates were collected by filtration, washed with a dilute alkaline aqueous solution and water, and dried. Then, the precipitates were recrystallized from toluene to obtain 3.3 g of n-butyl 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetate. Yield: 80.5% as calculated on the basis of 4-(2,3-dichlorophenyl)carbamoylacetic acid) Melting point: 132°-136° C.
Reaction SMILES: [OH:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[C:11]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.Cl.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[C:11]([CH3:19])[C:3]=1[CH2:4][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1cc(C)c(C(=O)CCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(CCCC(=O)O)c(O)c1OC

Procedure:
A mixture of 3-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)propionic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=2 in the free form) (0.536 part), zinc amalgam (1 part), concentrated hydrochloric acid (1 volume part), water (2 volume parts) and toluene (2 volume parts) was refluxed for 5 hours and, after cooling, the reaction mixture was extracted with diethyl ether. The extract was washed with water and dried. The solvents were distilled off under reduced pressure and the residue was recrystallized from diethyl ether-hexane. The procedure provided 4-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)butyric acid (formula II-2 wherein R=H3CO, X=H, Y=OH, n=2, in the free form) (0.34 part) as colorless needles melting at 98°-100° C.