Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44]([CH:54]=O)[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44](/[CH:54]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38][CH:37]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCC(C=O)CCc1ccc(C#N)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5.91 ml (9.45 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 1820 mg (4.05 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 15 ml of anhydrous THF at 0° C. Then, at this temperature, a solution of 1085 mg (3.38 mmol) of ethyl 8-(4-cyanophenyl)-6-formyloctanoate in 15 ml of THF is slowly metered in. After the reaction solution has been warmed to room temperature it is stirred for 12 hours and, after addition of some water, concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). 1150 mg (2.79 mmol, 83% of theory) of a colorless solid are obtained.
Reaction SMILES: [N:1]#[C:2][C:3]#[N:4].C#N.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=1.[OH-].[Na+]>CO>[Cl:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]=[C:2]([NH2:1])[C:3]([NH2:4])=[N:15]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: N#CC#N
Agent: C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2ccc(Cl)cc2nc1N
Reaction time: 48 h
Yield: 43 %

Procedure:
60 G (1.15 moles of cyanogen, which had beforehand been freed of adhering hydrocyanic acid by washing with a silver nitrate solution containing nitric acid and had been condensed in a cold trap, were passed at room temperature into a solution of 71.3 g (0.5 mole) of 1-chloro-3,4-diaminobenzene and 2 ml of 10% strength sodium hydroxide solution in 200 ml of anhydrous methanol. The reaction mixture was left to stand for 2 days at room temperature. Thereafter the resulting precipitate was filtered off, rinsed with a little methanol and dried. 41.6 G (representing 43% of theory) of 6-chloro-2,3-diamino-quinoxaline of melting point 290°C were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Yield: 83 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, step 2) (300 mg, 1.18 mmol), aniline (0.12 ml, 1.3 mmol) and p-toluenesulfonic acid (25 mg) in toluene (50 ml) was heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude brownish solid (420 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole (305 mg, 83%) as a white solid: mp (DSC) 148° C. Anal Calc'd. for C18H17NSO2 : C, 69.43; H, 5.50; N, 4.50; S, 10.30. Found: C, 69.18; H, 5.42; N, 4.42; S, 10.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH:23]([CH3:28])[CH2:24][N:25]([CH3:27])[CH3:26])[C:8](=O)[C:7]=2[CH:30]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH:23]([CH3:28])[CH2:24][N:25]([CH3:26])[CH3:27])[CH2:8][C:7]=2[CH:30]=1
Reactant: COc1cc2c(=O)n(C(C)CN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1cnc3cc4c(cc3c1N(C(C)CN(C)C)C2)OCO4
Yield: 45.4 %

Procedure:
The title compound was prepared as follows. 8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one (80 mg, 0.18 mmol; Example 7) in THF (150 mL) was added to LiAlH4 (50 mg, 1.3 mmol), and the mixture was stirred under nitrogen at reflux for 4 h. The reaction was quenched by the sequential addition of water (5 drops), 10% NaOH (5 drops), and water (5 drops). The mixture was filtered through Celite and evaporated, and the crude mixture was chromatographed on silica in 1.0% methanol in chloroform to give 35 mg of the reduced product, in 45.4% yield; mp 153-154° C.; 1H NMR (CDCl3) δ 1.16 (d, 3H, J=8), 2.38 (dd, 2H, J=12.2, 8.0), 3.68-3.80 (m, 1), 3.88 (s, 3H), 4.24 (s, 2H), 6.16 (s, 2H), 6.64 (s, 1H), 7.24 (s, 1H), 7.40 (s, 2H), 7.62 (s, 1H), 8.88 (s, 1H); 13C NMR (CDCl3) δ: 17.7, 45.6, 46.0, 56.2, 56.4, 57.8, 64.2, 100.1, 101.7, 105.8, 106.4, 108.5, 120.5, 120.6, 123.6, 126.9, 143.4, 146.6, 147.7, 148.9, 149.5, 149.6, 150.0; HRMS calcd for C24H27N3O4H 422.2002; found 422.2081.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](Cl)=[O:4].[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][C:3](=[O:4])[C:2](=[O:1])[C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:13]1
Reactant: CN1CCC[C@@H](O)C1
Reactant: O=C(Cl)C(=O)c1cccs1
Solvent: ClCCl
Product: CN1CCC[C@@H](OC(=O)C(=O)c2cccs2)C1
Reaction time: 0.33 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetyl chloride (8.9 g, 51.2 mmol) at 5° C. in DCM (50 ml) is added a solution of (R)-1-Methyl-piperidine-3-ol (5.87 g, 51 mmol) in DCM (50 ml), dropwise with stirring over 20 minutes. The resulting mixture is stirred for 18 hours at room temperature. Washing with 1 Molar sodium bicarbonate solution, drying over magnesium sulphate, filtration and evaporation then gives the title compound as a dark oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][C:13]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)(C(=O)OCC)C(C)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 1-carbethoxy-4-carbethoxy-4-cyclopropylamino-3-methylpiperidine. Yield 6.0 g (70%), C12H22N2O2, m/z 227 (M+1), PMR (CDCl3): 0.38 (m, 4H), 0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H) 2.32 (m, 1H), 2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m, 2H).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]3[CH2:25][CH2:26][CH2:27][C:28]4[S:32][CH:31]=[CH:30][C:29]=4[C:20]3=[N:19]2)=[CH:14][CH:13]=1>O(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]3[CH2:25][CH2:26][CH2:27][C:28]4[S:32][C:31]([CH:9]=[O:10])=[CH:30][C:29]=4[C:20]3=[N:19]2)=[CH:14][CH:13]=1
Reactant: CN(C=O)c1ccccc1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccsc1CCC2
Agent: ClOCl
Product: O=Cc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A mixture of 0.45 g of N-methylformanilide in 0.33 ml of phosphrus oxychloride was stirred at room temperature for an hour and 0.5 g of 2-(4 -chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one was added thereto. After stirring at room temperature for 2 hours, the mixture was poured into ice-cold water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :40 g) column using chloroform as an eluent. The resulting solid was recrystallized from a mixed solvent of chloroform and ethanol to give 0.25 g of 2-(4-chlorophenyl)-9-formyl-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]-cyclohepta[1,2-c]pyridazin-3-one as a pale yellow powder, melting at 170°-172° C.
Reaction SMILES: CC[O-].[Na+].O=[C:6]([CH2:13][C:14](=O)[CH2:15][CH2:16]C)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:19][NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH3:19][N:20]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:13]([CH2:14][CH2:15][CH3:16])=[N:21]1
Reactant: CNN
Reactant: CCCC(=O)CC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)n(C)n1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
76.5 g of 20% strength by weight sodium ethylate solution were initially introduced into a 250 ml 4-necked flask and 41.9 g of ethyl 2,4-diketoheptanecarboxylate were added in the course of 15 minutes. The solution thus prepared was added to a mixture of methylhydrazine (10.4 g), acetic acid (13.5 g) and ethanol (20 ml) at an internal temperature of 30 to 40° C. in the course of 45 minutes. When the addition was complete, the mixture was subsequently stirred at room temperature for a further hour and the ethanol was then distilled off. 100 ml of toluene and 100 ml of water were then added, the phases which form were separated and the aqueous phase was extracted twice more with 50 ml of toluene each time. The combined toluene extracts were reextracted with 100 ml of water, dried and concentrated under a slight vacuum. 31 g of isomer-free ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate having a boiling point of 125 to 128° C. under a pressure of 13 mm were obtained by fractional distillation. This corresponds to a yield of 75% of theory. The undesirable isomer ethyl 1-methyl-5-n-propyl-pyrazole-3-carboxylate was obtained as a second fraction in a yield of 6.2 g (=15% of theory). The boiling point of this isomer was 166 to 168° C. under a pressure of 13 mm.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O)(=O)C>C(Cl)Cl>[CH:13]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Yield: 68.7 %

Procedure:
Following the procedure of Example 2, 16.0 g of pyridinium chlorochromate, 10.0 g of (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 36.0 g of crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid in 250 ml of methylene chloride gives 6.8 g of the product as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])OC1>>[F:38][C:31]1[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:30]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CC1(C)COB(c2ccc(C#N)cc2F)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)cc4F)c3)cnc2c1F
Yield: 9 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-fluorobenzonitrile were coupled in the same way as in Example 30 to give 2,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (9 mg, 9%): δH (400 MHz, d6-DMSO) 1.56 (6H, s), 7.27 (1H, t, J 7), 7.60 (1H, t, J 9), 7.81-7.92 (5H, m), 8.05 (1H, d, J 10), 8.47 (1H, d, J 7); m/z (ES+) 408 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[NH:5][CH2:4][C:3]1([CH3:13])[CH3:12].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([N:5]1[C:6](=[O:11])[CH2:7][C:8]([CH3:9])([CH3:10])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)=[O:17]
Reactant: CN=C=O
Reactant: CN1C(C)(C)CNC(=O)CC1(C)C
Product: CNC(=O)N1CC(C)(C)N(C)C(C)(C)CC1=O

Procedure:
Using the same conditions as in Example 4, 2.76 parts of 1,2,2,7,7 -pentamethyl-1,4-diazacycloheptan-5-one and 0.93 parts of methyl isocyanate afforded a colourless solid which was crystallised from petroleum ether (of boiling range 60°-80°C) to give 4-methylcarbamoyl-1,2,2,7,7-pentamethyl-1,4-diazacycloheptan-5-one. This material had a melting point of 111°-113°C and gave the following elemental analysis by weight:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)C2(C)C
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-3-methyl-1,3-dihydro-indol-2-one (679 mg, 3.83 mmol) in THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by dropwise addition of 2.5M n-BuLi (3.06 mL, 7.66 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (275 μL, 4.40 mmol) and let stir for 30 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soin, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 35% ethyl acetate/hexanes) to give 601 mg of title compound as a white crystalline solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-ethoxy-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M36) (133 mg, 0.27 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (28 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1.[CH3:32]I.[Cl-].[NH4+]>C1COCC1>[CH3:32][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15][CH2:16][N:11]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (12.9 mL, 12.9 mmol, 1M solution in THF) at −78° C. was added to 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (3.0 g, 10.3 mmol) in THF (20 mL), and the reaction was stirred at this temperature for 20 minutes. MeI (0.867 mL, 13.9 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 5:1) to give 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.1 g, 98% yield) as an oil.
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([C:27]2[N:31]([C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:41])=[N:29][N:28]=2)=[CH:22][C:21]=1[CH:42]([CH3:44])[CH3:43])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>[Pd].C(O)C>[P:1]([OH:3])([OH:11])([O:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([C:27]2[N:31]([C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:41])=[N:29][N:28]=2)=[CH:22][C:21]=1[CH:42]([CH3:43])[CH3:44])=[O:2]
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CCC3)c(O)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CCC3)c(O)cc1OP(=O)(O)O
Yield: 86.9 %

Procedure:
A solution of 0.15 g (0.24 mmols) of 8 and 25 mg of Pd—C catalyst in 20 mL of anhydrous ethanol was subjected to hydrogenation conditions at 1 atm pressure for 2 h. The catalyst was filtered off and the crude product was reslurried in 98:2 mixture of diethylether:ethanol to afford 90 mg of the phosphate 9 as off white solid.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]([N:12]1[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]2[CH:20]([CH2:23][CH:24]=C)[CH2:21][CH2:22][C@H:14]2[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)=[O:28]>O.[Os](=O)(=O)(=O)=O>[CH2:2]([O:9][C:10]([N:12]1[C@@H:17]([CH3:18])[C:16](=[O:19])[N:15]2[CH:20]([CH2:23][CH:24]=[O:28])[CH2:21][CH2:22][C@H:14]2[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: C=CCC1CC[C@H]2CN(C(=O)OCc3ccccc3)[C@@H](C)C(=O)N12
Agent: O=[Os](=O)(=O)=O
Agent: [Na]
Solvent: O
Product: C[C@H]1C(=O)N2C(CC=O)CC[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium periodiate (206 mg, 0.96 mmol) and osmium tetroxide solution (2.5% in tert-butyl alcohol, 33 μL, 3.3 μmol) were added at 0° C. to a suspension of (3S,8aS)-6-allyl-3-methyl-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid benzyl ester (110 mg, 0.33 mmol) in acetone (1 mL) and water (1 mL). After removal of the ice bath the reaction mixture was stirred for 3 h at room temperature, then partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to furnish (3S,8aS)-3-methyl-4-oxo-6-(2-oxo-ethyl)-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid benzyl ester [MS: 331.2 (M+H)+]. This was dissolved in DCM (1 mL) and added at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (53 mg, 0.33 mmol), Et3N (33 mg, 0.33 mmol), HOAc (39 mg, 0.66 mmol), and sodium triacetoxyborohydride (77 mg, 0.36 mmol) in DCM (1 mL). After 16 h the reaction mixture was partitioned between EtOAc and 1 M aq. sodium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (88 mg, 62%). Light yellow gum, MS: 442.4 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.CN(C=O)C.[OH-].[Na+:23].O>C(O)C>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:23].[Na+:23].[Na+:23]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 86 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), absolute Ethanol (50 ml) and water (2.5 ml) [=5% v/v water in Ethanol]. The reaction mixture was heated to reflux temperature for 20 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2×25 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (86%) of Zoledronate trisodium crystal form XI (LOD by TGA=8.9%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:24][CH:25]=[C:26]([C:32](OCC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.O>CN(C)C=O>[O:24]=[C:25]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:32]=[C:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)-quinazoline (4.4 g) and diethyl ethoxymethylenepropanedioate (5.5 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 3 hours. To the reaction mixture was added water. The resulting crystals were collected by filtration, washed with water, and suspended in dichloroethane under heating. After the suspension was cooled to ambient temperature, the resulting crystals were collected by filtration and washed wit dichloromethane. There was obtained ethyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]-quinazoline-3-carboxylate (2.4 g). The filtrate was concentrated to 1/4 of its original volume and cooled to 0° C. to yield an additional 0.37 g of the same product. The cryde substance (2.77 g) obtained above was chromatographed on silica gel with 2% methanol-dichloromethane. The product was recrystallized from a mixture of methanol and dichloromethane to give crystalline pure product (2.45 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:17][C:16]([NH:1][C@@H:2]([C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][O:14][CH3:15])=[O:18]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The (R)-2-amino-N-benzyl-3-methoxypropionamide solution prepared above was cooled to <5° C. and acetic anhydride (10 ml, 0.106 mol) added at <15° C. The reaction mixture is warmed to room temperature over 30 minutes and aged for a further 30 minutes. The mixture is then washed with water (44 ml), 8% sodium bicarbonate (44 ml) and water (44 ml). The methylene chloride was exchanged for ethyl acetate by distillation and the solution distilled to a volume of 115 ml. The product was crystallized by cooling the solution to 0-5° C. and the pure Lacosamide isolated by filtration (18.7 g, 69.8%) HPLC purity 99.98%, Chiral purity 99.8% ee.