Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Yield: 63.8 %

Procedure:
4-methyl-3-nitrobenzaldehyde (0.270 g, 1.60 mmol) and anhydrous CuCl2 (0.435 g, 3.20 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.400 g, 1.60 mmol) in anhydrous EtOH (10 mL). After heating at reflux temperature for 3 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 60% EtOAc in heptane, afforded 3-(4-chlorophenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.400 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[N:39]1([CH2:44]/[CH:45]=[CH:46]/[C:47](O)=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:47](=[O:48])/[CH:46]=[CH:45]/[CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)/C=C/CN1CCCC1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)/C=C/CN3CCCC3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 2b, 19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and (E)-4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride (9.45 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford 7.1 mg of (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (26.8% yield). Data: UPLC (C) Rt: 1.25 min; m/z 537.4 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][CH:8]([CH:11]=[CH2:12])[CH2:9]O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:9][CH:8]([O:7][CH3:6])[CH:11]=[CH2:12])(=[O:3])[CH3:2]
Reactant: C=CC(CO)OC
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C=CC(COC(C)=O)OC
Temperature: 60 °C

Procedure:
In a 3-liter, 3-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet, temperature probe and vigoreux column was placed 1200 mL toluene, sodium acetate (88.59 g, 1.08 mol) and 2-methoxy-3-buten-1-ol (250.0 g, 2.45 mol). Mixture heated to 60° C. with stirring. Once temperature had stabilized, acetic anhydride (288.83 g, 2.80 mol) added dropwise over 2.5 hours. Maintained temperature for 1.5 hrs then increased temperature to 70° C. for 1 hour. Gas chromatography showed no trace of starting material in reaction. Began cooling reaction to room temperature. When reaction had cooled to 38° C., one liter of a 5% sodium bicarbonate solution was added at high speed to decompose any excess acetic anhydride remaining in the reaction. Extracted reaction twice with water, layers separated, the aqueous layer extracted twice with toluene and added to the organic layer. Organic layer dried with anhydrous magnesium sulfate, filtered and concentrated by rotovap. Yield 222.43 g (63.0%) of a clear, colorless material. 1H NMR consistent with 1-acetoxy-2-methoxy butene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH2:15]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[N:25]=1)=[O:5]
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cccc3Cl)n2)CC1
Product: Cl
Yield: 45 %

Procedure:
Using a method similar to example 1, using 2-chloro-6-fluoro-benzoyl chloride (116 mg, 0.60 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) provides the free amine of the title compound as a colorless oil (78 mg, 45%): MS (ES): m/z=374.1 (M+H)+; 1H NMR (CDCl3): δ 9.03 (s, br, 1H), 8.26 (d, 1H), 7.73 (t, 1H), 7.30 (m, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.98 (dt, 1H), 6.62 (m, 1H), 2.58 (m, 1H), 2.38 (m, 3H), 2.34 (s, 6H), 2.15 (m, 2H), 1.53 (m, 1H). Using a salt formation method similar to that in example 1 provides the di-hydrochloride salt.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N1C=CN=C1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][C:24]#[N:25])=[CH:21][CH:20]=1.[OH:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[C:24]([CH2:23][C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:1]([N:31]([CH2:30][CH2:29][OH:28])[C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=2)=[O:2])=[CH:20][CH:21]=1)#[N:25]
Reactant: COC(=O)Cc1ccc(NCCO)cc1
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N(CCO)C(=O)Nc2ccc(CC#N)cc2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.46 g of carbonyldiimidazole and 1.04 g of imidazole were dissolved in 20 ml of tetrahydrofuran. The mixture was cooled to 0° C. and 1.18 g of 4-amino-benzylcyanide were added. After about 3 minutes a solution of methyl 4-[(2-hydroxy-ethyl)-amino]-phenylacetate in 7 ml of tetrahydrofuran was rapidly added dropwise, the ice cooling was taken away and the mixture was stirred for 16 hours at ambient temperature (a precipitate formed initially was filtered off). The mixture was concentrated down, the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid and water and the organic phase was evaporated down. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/methylene chloride=1:1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].N1CCCCC1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[CH:29][C:30]#[N:31]>CCO>[NH2:15][C:14]1[N:23]2[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:29]([C:30]#[N:31])[CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[C:13]=1[C:12]#[N:16]
Reactant: N#CC=C1CCCCN1
Reactant: N#CCC#N
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC1=C(N)N2CCCCC2=C(C#N)C1c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a mixture of 1H-indazole-5-carboxaldehyde (200 mg, 1.37 mmol), from Synthetic Preparation 1, and malononitrile (100 mg, 1.51 mmol) in EtOH (5 mL) was added piperidine (0.2 mL). The mixture was stirred at rt for 2 hr, after which the solid (140 mg) was collected by filtration. This solid and 2-piperidinylidene-ethanenitrile (100 mg, 0.82 mmol; per Synthetic Preparation 5) were combined in EtOH (5 mL). The resulting mixture was kept at 90° C. for 1 hr. After cooling to rt, the solvent was removed in vacuo. The residue was purified on flash column (silica gel) and crystallized further in acetate to afford 4-amino-6,7,8,9-tetrahydro-2-(1H-indazol-5-yl)-2H-quinolizine-1,3-dicarbonitrile (110 mg, 25.4%) (Cpd. No. 305). 1H-NMR (400 MHz, CD3OD): δ=8.02 (s, 1H), 7.58 (s, 1H), 7.53 (d, 1H), 7.34 (d, 1H), 4.53 (s, 1H), 3.63 (d, 2H), 2.72 (m, 2H), 1.95 (m, 1H), 1.73-1.88 (m, 3H) ppm.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.[C:30]([NH:40][C@H:41]([C:45]([O:47][CH2:48][CH:49]([O:69][C:70](=[O:76])[CH2:71][CH2:72][C:73](O)=[O:74])[CH2:50][O:51][C:52](=[O:68])[C@H:53]([CH:65]([CH3:67])[CH3:66])[NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:73](=[O:74])[CH2:72][CH2:71][C:70]([O:69][CH:49]([CH2:50][O:51][C:52](=[O:68])[C@H:53]([CH:65]([CH3:67])[CH3:66])[NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[CH2:48][O:47][C:45](=[O:46])[C@H:41]([CH:42]([CH3:44])[CH3:43])[NH:40][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:76])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)CCC(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2′,3′dideoxy-3′-fluoroguanosine (17.8 g, 66 mmole), HOBT (10.64 g, 78.8 mmole), succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester (52 g, 78.8 mmole) and DMAP (0.96 g, 7.88 mmole) was coevaporated two times with DMF and reduced to about 500 ml. DCC (17.3 g, 84 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was warmed for six hours at 60° C. and then cooled to about 10° C. The mixture was filtered and the solution was reduced under reduced pressure. 1200 ml of ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 42 g.
Reaction SMILES: [H-].[Na+].[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[C:9]1([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]2[CH2:19][C@@H:18]([OH:20])[C@@H:17]2[CH3:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H].F[C:31]1[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][CH:36]=1>CN(C=O)C>[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[C:22]1([CH:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:16]2[CH2:19][C@@H:18]([O:20][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C@@H:17]2[CH3:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](Oc2cccc(C(F)(F)F)c2)CN1C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
A stirred slurry of 1.2 g (0.03 mole) of sodium hydride (60% dispersion in mineral oil) in 50 ml of dry DMF was treated with 3.45 g (0.01 mole) of trans-1-diphenylmethyl-2-methylazetidin-3ol oxalate added in small portions. When the addition was complete and the evolution of hydrogen ceased, the reaction was heated to 80° C. for 2 hr then 1.64 g (0.01 mole) of 3-fluoro-trifluoromethylbenzene was added dropwise. The reaction mixture was stirred at 80° C. for an additional 18 hr. The reaction mixture was diluted with ice water and extracted with 3×25 ml of toluene. The extracts were combined, dried over magnesium sulfate, filtered, and the filtrate treated with 1 g of oxalic acid. The resulting solid was collected by filtration. Recrystallization from acetone-isopropyl ether yielded 2.2 g (4.5%) of fine white crystals, m.p. 146°-147° C. Proton NMR shows it to be the trans compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCCCN1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCC1CCCCN1Cc1ccccc1

Procedure:
To a stirred solution of compound 13 (3.6 g, 15.00 mmol) in chloroform (50 mL) was added thionyl chloride (1.34 mL) at 0° C. The reaction mixture was heated at reflux for 2 hours and then concentrated. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane to provide compound 14 as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:17])[CH3:18])[C:6]=2[CH:5]=1)[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1)[CH3:2]
Reactant: CCNc1ccc2c(c1)C(C(C)C)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(c1ccc2c(c1)C(C(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 20.4 %

Procedure:
To a mixture of 85 mg (0.35 mmol) of ethyl-(8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 168) and 0.10 g (0.71 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. Purification was done using flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (26 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:7]([OH:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].O1CCCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(OCC)(=O)C.O>[CH2:24]([O:23][C:21]([NH:1][C@@H:2]([C@@H:7]([OH:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)[C@H](C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (2S,3S)-methyl 2-amino-3-hydroxybutanoate (2.5 g, 14.73 mmol) in a 1:1 mixture of tetrahydrofuran and water (50 mL), sodium bicarbonate (1.9 g, 22.10 mmol) was added and the mixture was cooled to 0° C. and to this benzyl chloroformate (2.76 g, 16.21 mmol) was added drop wise over a period of 30 minutes. The mixture was then stirred at the room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (25 mL), organic layers were separated, washed with brine (25 mL) and dried over sodium sulfate. Removal of solvents under vacuum afforded the crude product which has been purified by silica gel column chromatography (230-400 mesh) using a gradient of ethyl acetate in pet.ether. Yield: 3.4 g (86%)1H NMR (400 MHz, DMSO-d6) δ: 1.09 (d, 3H), 3.89 (s, 3H), 3.99 (t, 1H), 4.01-4.06 (m, 1H), 5.00 (d, 1H), 5.04 (s, 2H), 7.30-7.40 (m, 5H), 7.63 (d, 1H). MS (ES) MH+: 268.1 for C13H17NO5.
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: OP(O)O
Reactant: O=C(O)Cc1cccnc1
Solvent: ClP(Cl)Cl
Solvent: CC#N
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: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([SH:18])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:14]2[N:13]=[C:12]([NH2:11])[CH:17]=[CH:16][N:15]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: Nc1ccnc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nccc(N)n2)s1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (2.2 g), 4-amino-2-mercaptopyrimidine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (50 ml) was heated at 90° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitation was collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.3 g, yield: 48.7%). mp: 255°-258° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([NH:34][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCC(=O)NCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a solution of 10.80 g (0.060 mole) of 3-(4-methoxyphenyl) propanoic acid and 6.57 g (0.065 mole of triethylamine in 25 ml dichloromethane at about 0.5° C., 6.84 g (0.063 mole) of ethyl chloroformate was added dropwise. The mixture was stirred for about 15 minutes at a temperature of about 5° to 10° C., then 6.96 g (0.065 mole) of benzylamine were added. The resulting mixture was stirred for about thirty minutes, and the solvent was evaporated. The residue was slurried in 5% aqueous sodium hydroxide. The solid was collected by filtration and rinsed with water until neutral. The washing process was repeated using 5% hydrochloric acid. The residue was dried under vacuum to give 11.0 g of the above-identified product, melting point 92°-94° C., which was suitable for use in step (b).
Reaction SMILES: [N+:1]([C@@H:3]1[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])#[C-:2].C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:26][C:25]([C@:3]1([N+:1]#[C-:2])[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (106.9 mg) in tetrahydrofuran (2.1 ml) was added dropwise a solution of n-butyl lithium (0.375 ml of 1.38 M solution in hexane) at -78° C. After stirring for 15 minutes at -78° C., the reaction mixture was added with a solution of acetone (0.0385 ml) in tetrahydrofuran (0.3465 ml) at -78° C. After stirring for 25 minutes at -78° C., the reaction mixture was added with acetic acid (0.0493 ml) at -78° C., diluted with ethyl acetate (30 ml), and washed with chilled brine (10 ml), aqueous sodium bicarbonate (10 ml), brine (10 ml), and saturated aqueous sodium chloride (10 ml). After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil was chromatographed on silica gel (1.2 g) eluting with a mixture of ethyl acetate and hexane (1:5-1:3) to give methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (96.5 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Yield: 71.9 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-(4-fluorobenzyl)-2-methylthio-4-pyrimidone (0.75 g) were refluxed in pyridine (3 ml) for 24 hours. The pyridine was removed in vacuo and the residue triturated with ethanol (5 ml) giving a colourless solid. The solid was recrystallised from methanol giving 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone (0.96 g) m.p. 172°-3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])[CH:13]=1)[CH3:11]>CN(C)C=O>[ClH:18].[CH2:10]([C:12]1[N:17]=[C:16]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:15]=[C:14]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])[CH:13]=1)[CH3:11]
Reactant: CCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 64.2 %

Procedure:
After 2-methyl-4-fluoroaniline(0.77 ml, 6.93 mmol) was added to a mixture solution of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.0 g, 3.47 mmol) and dimethylformamide(5 ml), 0.92 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.