Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 55.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 358 mg of 4-fluoro-3-(trifluoromethyl)aniline in place of the 2,4-difluoroaniline. 222 mg of N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[C:14]#[N:15]>C(O)C.[Pt]=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:4]2[C:3]=1[C:14]([NH2:15])=[N:6][CH2:5]2
Reactant: COc1cc(C#N)c(C#N)c(F)c1OC
Agent: O=[Pt]
Solvent: CCO
Product: COc1cc2c(c(F)c1OC)C(N)=NC2
Reaction time: 72 h
Yield: 43.6 %

Procedure:
After dissolving 3-fluoro-4,5-dimethoxyphthalonitrile (450 mg, 2.18 mmol) in ethanol (50 ml), platinum oxide (0.1 g) was added. Catalytic hydrogenating reduction was carried out for 3 days at normal temperature and pressure. The catalyst was removed by celite filtration, washing was performed with methanol, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent: ethyl acetate:methanol:27% aqueous ammonia=3:1:0.1) to yield the title compound as a brown solid (200 mg, 43%).
Reaction SMILES: O[C:2]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([CH:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=[O:8])[C:3]([OH:5])=O>C(OC(=O)C)(=O)C>[O:13]1[CH2:14][CH2:15][CH:10]([C:6]2[C:7](=[O:9])[O:8][C:3](=[O:5])[C:2]=2[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:11][CH2:12]1
Reactant: O=C(O)C(C1CCOCC1)C(O)(C(=O)O)C1CCOCC1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C(C2CCOCC2)=C1C1CCOCC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
2-Hydroxy-2,3-bis(tetrahydro-2H-pyran-4-yl)succinic acid (1.2 g, 3.98 mmol) was dissolved in acetic anhydride (15 ml), and the solution was stirred at 120° C. for 24 hr. Excess acetic anhydride in the reaction mixture was removed by distillation under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=40:60) to give the title compound as a colorless solid (0.6 g, yield 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[OH:14][NH:15][C:16](=[NH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[OH:14][N:15]=[C:16]([NH:22][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=N)NO
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(=NO)NC(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92.4 %

Procedure:
To 5-methyl-2-nitro-benzoic acid (100 mg, 0.55 mmol), ethyl 2-(hydroxyamino)-2-imino-acetate (73 mg, 0.55 mmol), and HATU (210 mg, 0.55 mmol) were added acetonitrile (4 mL) and DIEA (96 μL, 0.55 mmol). The reaction was stirred at room temperature for 25 min resulting in a thick white precipitate. The solid was filtered, washed with water then dried to yield ethyl 2-(hydroxyimino)-2-(5-methyl-2-nitrobenzamido)acetate as a white solid (150 mg, 92% yield). LC/MS m/z 296.1 [M+H]+. 1H NMR (400.0 MHz, DMSO-do) δ 8.05 (d, J=8.3 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.16 (br s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:3].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=C(C)CCCCCCCCC
Product: CCCCCCCCCC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-1-undecene (35.6 g, 211 mmoles), parabromphenol (36.6 g, 211 mmoles) and Dowex 50×12 resin (100-200 mesh) previously washed with water, rinsed with acetone and oven dried for 3 hours at 80° C., is heated at 100°-110° C. for 48 hours. The mixture is then cooled to ambient temperature and chromatographic on a silica column (eluant: a mixture of dichloromethane, 40% and hexane, 60%), yielding 4-bromo-2-(1,1-dimethyldecyl)-phenol in the form of a pale yellow oil. (30.85 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([O-:16])=[O:15])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([OH:16])=[O:15])[O:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Br)CCOC2C(=O)[O-]
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)CCOC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate (12 g, 38 mmol) in 50 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (4.79 g, 114 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and to the residue was added 50 mL of water and the mixture was extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]4)[CH:12]=2)[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[CH2:29](I)[CH3:30].C(N(CC)CC)C>C1COCC1>[CH2:29]([N:5]1[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]4)=[CH:10][CH:9]=2)[CH:4]1[CH:1]([CH3:3])[CH3:2])[CH3:30]
Reactant: CC(C)C1NCCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc21
Reactant: CCI
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc2C1C(C)C

Procedure:
A solution of Example 20A (240 mg, 0.66 mmol), ethyl iodide (0.11 mL, 1.32 mmol), and triethylamine (0.18 mL, 1.32 mmol) in THF at 45° C. was stirred for 4 hours and concentrated. The concentrate was purified by flash column chromatography with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[N:17]2[C:18](=[O:35])[C@@H:19]([N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20][CH2:21][C:22](=[O:23])[N:16]2[CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:1]([NH:9][C:10]([C@H:12]1[N:17]2[C:18](=[O:35])[C@@H:19]([NH2:24])[CH2:20][CH2:21][C:22](=[O:23])[N:16]2[CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: CCO
Product: N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCCc3ccccc3)N2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a mixture/suspension of (1S,9S)-9-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide (310 mg, 0.70 mmol) and hydrozinehydrate (70 mg, 1.40 mmol) in ethanol (10 mL) is stirred at 60° C. for 2 hours. After cooled to room temperature and concentrated, the reaction mixture is purified by chromatography (CH2Cl2/MeOH:97/3) to give (1S,9S)-9-amino-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide (240 mg, 99%) as white solid. (NMR and MS data confirmed, U-3133-67).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.Cl.CCOC(C)=O>P([O-])([O-])([O-])=O.CC(O)C.C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH2:6][C@@H:5]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:35])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 48 h
Yield: 40.3 %

Procedure:
To a stirred solution of the Altus catalyst #8 (10.0 g) in phosphate buffer (pH 7, 500 mL) was slowly added 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester from Example 508 (10.0 g, 0.0196 mol) in IPA/toluene (40 mL/15 mL) for over 30 min to form a slurried reaction mixture. The reaction was monitored at 2 day intervals using chiral HPLC. After 24 days, the reaction mixture was adjusted to pH 1-2 using 1 N HCl, and then EtOAc (300 mL) was added. The mixture was stirred vigorously for 1 h. The emulsion was filtered through a pad of CELITE®, washing with EtOAc (75 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by filtration chromatography (silica gel column: 14 cm OD, 10 cm in height, 1% MeOH/20% EtOAc/hexanes). After the unreacted pyrazole ester (4:1 R/S) was recovered (6.0 g, 60%), the eluent was changed to 2-3% MeOH/50% EtOAc/hexanes to obtain the desired pyrazole acid (3.8 g, 40%) as an oil. Chiral HPLC (Method S): Rt (S enantiomer)=8.1 min. MS (ES+): mass calculated for C26H22Cl2N2O3, 480.10; m/z found, 480.8 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08 (dd, J=9.6, 5.8 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J=14.9, 9.6 Hz, 1H), 3.13-3.08 (dd, J=14.9, 5.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOCC.[ClH:33]>CO>[ClH:1].[ClH:33].[CH:20]1([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCCC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(Nc1nc2cccc(NC3CCCCCC3)n2n1)c1cccnc1
Yield: 42 %

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 296 mg; 1.08 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL). The parent compound was dissolved in MeOH and Et2O/HCl was added. The precipitate obtained was filtered, washed with Et2O and dried under reduced pressure at 40° C. to give the title compound as a white powder (178 mg, 42%). HPLC, Rt: 2.98 min. (purity 99.7%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4. CHN analysis: [C19H22N6O.2.0 HCl.1.5H20] Corrected: C, 50.67%; H, 6.04%; N, 18.66%. Found: C, 50.69%; H, 5.97%; N, 18.61%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:33][CH3:34])(=[O:10])=[O:9])=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[S:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C>[Cl:35][C:4]1[CH:3]=[C:2]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][CH:39]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:33][CH3:34])(=[O:10])=[O:9]
Reactant: Cc1ccc(B(O)O)s1
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccc(C)s2)cc1Cl
Yield: 85.8 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-{[(4-bromo-2-chlorophenyl)sulfonyl]amino}-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D13) (0.10 g, 0.169 mmol), 5-methylthiophen-2-boronic acid (0.0739 g, 0.254 mmol), Palladium dichloride di-triphenylphosphine (5.9 mg, 0.0127 mmol), sodium carbonate (0.0359 g, 0.339 mmol) were heated in DME (1 mL) and water (0.5 mL) at 120° C. in the microwave for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4) and evaporated to give a yellow foam which was purified by chromatography [silica gel, eluting with 0 to 70% Ethyl acetate/pentane]. Product fractions evaporated to give a pale yellow oil (D16) (0.088 g) MS (ES+) m/e 607/609 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O

Procedure:
1 mol of 6-hydroxy-1-tetralone, 1.2 mols of methyl chloroacetate, 2 mols of potassium carbonate and 0.1 mol of potassium iodide are boiled under reflux in 2 1 of butanone for 6 hours. The mixture is filtered, the residue is rinsed with acetone and the filtrate is evaporated. The residue is taken up in methylene chloride, and the mixture is washed 3 times with 0.5 N NaOH solution, dried over sodium sulphate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+:17]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[K+:17]
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])c1ccc(Cl)cc1
Yield: 84.1 %

Procedure:
The procedure of Example 1 was followed using methyl 4-chlorobenzoate (13.65 g, 80 mmol), potassium trimethylsilanolate (10.26 g, 80 mmol), dry ether (500 mL) and a 4 h reaction time. Potassium 4-chlorobenzoate (13.1 g, 84% yield) was isolated as a white solid: 1H NMR (D2O, DSS, 80 MHz) δ 7.68 ppm (ABq, Δν1-3 =29 Hz, J=8.5 Hz, Ar--H's, 4H). Anal. Calcd. for C7H4ClKO2 : C, 43.19; H, 2.07. Found: C, 43.27; H, 2.33.
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])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:33])[N:24]([CH3:32])[CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:35]>CCOC(C)=O>[ClH:35].[CH3:32][N:24]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:23]([C:12]1[C:13]2[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:33]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)Cc3cccnc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N(C)Cc3cccnc3)c2c1
Yield: 100 %

Procedure:
As described in example 1, 88 mg of [6,8-dimethoxy-4-(methyl-pyridin-3-ylmethyl-carbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 102 mg (>100%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid methyl-pyridin-3-ylmethyl-amide hydrochloride. MS: APCI (M+H) calc'd for C21H24N4O3+H 381.4; found 381.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>C(#N)C>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Solvent: CC#N
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
3-Pyridine acetic acid (100 g) added to acetonitrile (1.0 L). To the reaction mixture was added phosphorous acid (142 g). The reaction mass was heated up to reflux temperature (70-75° C.). To this phosphorous trichloride (271 g) was added slowly at 70° C. and the reaction mass was refluxed for 5.0 hours. The solvent was distilled off completely under vacuum. Demineralized water (400 ml) was added to the reaction mass at ambient temperature and charcoalised. The filtered mass was refluxed for 4.0 hours at 85° C. The reaction mass was cooled to 0-5° C. and stirred for 2 hours. It was filtered and washed with demineralized water to get risedronic acid as a white crystalline solid. The wet material was dissolved in demineralized water (300 ml) and 50% sodium hydroxide solution was added to reaction mass to make the pH basic, charcoalised and acidified with concentrated hydrochloric acid. The reaction mass was stirred further for 1.0 hour. The solid was filtered, washed with demineralized water to get the pure risedronic acid (160 g, yield 77.33%) having purity of 99.25% by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C.C(O)C>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=1)=[O:7]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)nc1C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1C

Procedure:
A mixture of 4-amino-N-(5,6-dimethylpyridin-2-yl)-3-nitrobenzamide (470 mg, 1.64 mmol) and of 5% platinum on carbon (60 mg) in 50 mL of ethyl acetate/ethanol (1:1) was stirred in under a hydrogen balloon. When the reaction was complete by LC/MS, the mixture was filtered through Celite to remove catalyst, and the filtrate was removed under reduced pressure to afford 3,4-diamino-N-(5,6-dimethylpyridin-2-yl)-benzamide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:20]([O-:22])=[O:21])=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])O
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1c(Cl)[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
15 g of (1) was added to a mixture of 150 ml acetic acid and 150 ml of acetic anhydride at 0°. 3.5 ml of 100% HNO3 was slowly added, and after 1 hour another 3.5 ml of 100% HNO3 was added. Stirring was continued for 1 hour at 0° C. The mixture was then added to ice, left in the cold overnight, and filtered to give 10 g of (65), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Yield: 69.6 %

Procedure:
Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A, 0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.50 g of (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10% MeOH/CH2Cl2), white solid, 70% yield]. 1H-NMR (MeOH, 250 MHz, δ): 7.45-7.27 (m, 5H, ArH); 6.96 (d, 8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 1H, CH); 0.98-0.85 (m, 2H, CH2).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])=[CH:22][C:21]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>CN(C)C=O>[N+:37]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])[CH:35]=[CH:36][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:39])=[O:38]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (J.Med. Chem. 1998, 2157) (0.8 g), 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.9 g) and triethylamine (0.8 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 72 h. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the organic layer was evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. The residue was triturated from methanol, yield 0.4 g as a solid.