Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=O)[CH:2]=[CH2:3].C1(P(=[CH:40][C:41]([O:43][CH3:44])=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=[CH:40][C:41]([O:43][CH3:44])=[O:42])[CH:2]=[CH2:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=CC(=O)OC
Temperature: 20 °C

Procedure:
A solution containing 16.3 g of (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-one in 200 cm3 of toluene was stirred under reflux with methyl (triphenylphosphoranylidene)acetate, under an inert atmosphere, for 16 hours. After cooling to about 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained, solubilized in 50 cm3 of dichloromethane in the hot state, was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45μ; diameter 10 cm; height 45 cm), eluting with a cyclohexane-ethyl acetate (80/20 by volume) mixture. 250-cm3 fractions were collected. Fractions 13 to 15 were combined and then concentrated as above. 5.8 g of methyl (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylidenacetate (Z isomer) were obtained in the form of a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([N:44]2[CH2:49][CH2:48][C@:47]([CH2:56][C:57]([CH3:61])([CH3:60])[C:58]#[N:59])([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:46][C:45]2=[O:62])[CH3:43])=[CH:38][CH:37]=1>>[CH3:60][C:57]([CH3:61])([CH2:56][C@:47]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:46][C:45](=[O:62])[N:44]([C@H:42]([C:39]2[CH:40]=[CH:41][C:36]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:37][CH:38]=2)[CH3:43])[CH2:49][CH2:48]1)[C:58]#[N:59].[OH:1][C:2]([CH3:33])([CH3:34])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
2,2-Dimethyl-3-(3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-2-oxo-(S)-6-phenyl-[1,3]oxazinan-6-yl)-propionitrile was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described Example 71 Method 2 to prepare 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile. (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one, is obtained from coupling (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one with 5-iodo-1-methyl-1H-pyridin-2-one by the action of Pd(PPh3)4 and 2 M aqueous Na2CO3 solution in a mixture of methanol and dioxane (1:3) at 80° C. The compound that had been obtained as a foam was dissolved in a small amount of ethyl acetate and stirred overnight at rt. The solid was filtered by suction, washed with a small amount of diethylether and dried. Melting point: 143-145° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:11]([O:10][C:2]([CH:3]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: BrCCCCCCCOc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCOc1ccccc1)C(=O)OCC
Yield: 63 %

Procedure:
Sodium (0.22 g, 9.6 mmol) was dissolved in EtOH (20 mL). Diethyl malonate (1.53 g, 9.6 mmol) in EtOH (5 mL) and 7-phenoxyheptyl bromide (2.36 g, 8.7 mmol) in EtOH (5 mL) were subsequently added at room temperature. The reaction mixture was refluxed for 8 h. After evaporation of the solvent, the residue was taken up in ethyl acetate (150 ml). The organic phase was washed with water (2×50 mL), and brine (50 mL), and dried over Na2SO4. The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.92 g, 63%), bp 150-154° C./0.1 torr, 1H-NMR: 1.24 (t, 6H), 1.1-1.8 (m, 12H), 3.30 (t, 1H), 3.91 (t, 2H), 4.18 (q, 4H), 6.7-7.2 (m, 5H).
Reaction SMILES: N=C=N.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=S.CS(Cl)(=O)=O.C(N(CC)CC)C>>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Cl)c1O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 103.3 %

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2-chlorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (311 mg, 0.58 mmol), methanesulfonyl chloride (0.09 mL, 1.16 mmol) and triethylamine (0.15 mL, 1.16 mmol) were reacted to form the desired product (300 mg, crude). 1H NMR (CDCl3) δ 0.37 (s, 6H), 1.03 (s, 9H), 2.87 (s, 6H), 7.05 (d, 1H), 7.12 (t, 1H), 7.22 (m, 2H), 7.34 (d, 1H), 7.42 (d, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:36]([O-:38])=[O:37])=[C:9]([C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([O:31][CH3:32])[C:20]=2[N+:33]([O-:35])=[O:34])[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>>[CH3:32][O:31][C:21]1[C:20]([N+:33]([O-:35])=[O:34])=[C:19]([C:9]2[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:8]=2[N+:36]([O-:38])=[O:37])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: NCCO
Reactant: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(OC)c2[N+](=O)[O-])c1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c2[N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
First, one mole of ethanolamine is reacted with each mole of 3,3'-dimethoxy-2,2',4,4',6,6'-hexanitrobiphenyl under the conditions given in example 6 to give 3-methoxy-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl (compound X). Compound X is then reacted with ammonia under the conditions of example 7 to produce 3-amino-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl (compound XI). Compound XI is then nitrated under the conditions of example 8 to produce the product 3-amino-3'-(hydroxyethylaminonitrate)-2,2',4,4',6,6'-hexanitrobiphenyl.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([NH:34][CH2:35][CH2:36][O:37][CH3:38])[C:31]([C:39]#[N:40])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.O.Cl>C1COCC1>[C:39]([C:31]1[C:32]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:40]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N
Reaction time: 0.67 h

Procedure:
A solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 74, 3.10 g, 5.43 mmol) in THF (40 ml) was treated with H2O (30 ml) followed by dropwise addition of conc. HCl (10 ml) and stirred for 40 min. The reaction mixture was quenched by addition of sat. aq. NaHCO3 (gas evolution) and then extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with EtOAc (25 ml) and sonicated until a white suspension was obtained. Then, heptanes (25 ml) was added and the resulting suspension was filtered. The solid was washed with heptanes and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=O)[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[S:39])[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(=S)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Yield: 179.8 %

Procedure:
A stirred mixture of 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromen-4-one (200.0 mg, 0.51 mmol), Lawesson's reagent (122.7 mg, 0.30 mmol) and anhydrous toluene (3.5 mL) was refluxed under N2 for 1 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (EtOAc/MeOH/NEt3, 40/2/1) to give 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromene-4-thione (222.0 mg, 100.0% yield) as a red solid and was used in next step without further purification. MS (ES+): m/e 412.1(M+H). HPLC/Method A (Rt 5.59 min, 74.0% purity).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:31])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 35.8 %

Procedure:
A solution of 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester (prepared in Example 22, 100 mg, 0.23 mmol) in diethyl ether (3 mL) at 0° C. under nitrogen was slowly treated with lithium aluminum hydride powder (12 mg, 0.30 mmol). The resulting reaction mixture continued to stir at 0° C. and was allowed to gradually warm to 25° C. The reaction mixture was then stirred at 25° C. over a period of 64 h. The reaction mixture was slowly quenched by the dropwise addition of water (5 mL). The resulting reaction mixture was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide (33 mg, 36%) as a white solid: mp 67-70° C.; EI-HRMS m/e calcd for C26H28N2O2 (M+) 400.2151, found 400.2147.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9]S(C)=O.[CH:14](=O)[CH3:15].N1CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][C:15]1[O:1][C:2]2[C:3]([C:8](=[O:13])[CH:9]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC=O
Reactant: CS(=O)CC(=O)c1ccccc1O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1cc(=O)c2ccccc2o1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
In an atmosphere of argon, 19.5 g (107.0 mmols) of 2'-hydroxy-2-(methylsulfinyl)acetophenone, 5.65 g (3.4 equivalent) of acetaldehyde and 5.0 ml (0.05 equivalent) of piperidine were dissolved in 500 ml of toluene, and the mixture obtained was refluxed with heating for 1 hour and 45 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the toluene. The residue thus obtained was dissolved in 300 ml of ethyl acetate and washed twice with 200 ml of water. The organic layer thus formed was dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=4/6) to obtain 14.7 g of 2-methylchromone (yield: 86%; a pale-white pink solid). 1H-NMR Spectrum [δ(ppm)]: 2.39(s, 3H), 6.17(s, 1H), 7.37(m, 2H), 7.64(dt, 1H, J=1.7 Hz, 8.1 Hz), 8.18(dd, 1H, J=1.7 Hz, 8.1 Hz)
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:46][CH:47]3[CH2:52][CH2:51][C:50]([F:54])([F:53])[CH2:49][CH2:48]3)=[CH:37][C:38]([F:45])=[C:39]([CH:44]=2)[C:40]([O:42]C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:46][CH:47]3[CH2:52][CH2:51][C:50]([F:54])([F:53])[CH2:49][CH2:48]3)=[CH:37][C:38]([F:45])=[C:39]([CH:44]=2)[C:40]([OH:42])=[O:41])[CH2:33][CH2:34]1
Reactant: COC(=O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: O=C(O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6, and making variations as required to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with methyl 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate, the title compound was obtained as a colorless solid (0.32 g, quant. yield): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.4 Hz, 1H), 6.58 (d, J=12.7 Hz, 1H), 4.60 (br s, 1H), 2.20-1.92 (m, 9H), 0.94-0.88 (m, 2H), 0.65-0.60 (m, 2H); MS (ES−) m/z 313.2 (M−1).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:26][CH2:25][CH2:24][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:20]1[C:19]2([CH2:24][CH2:25][CH2:26][C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:27])=[O:2])=[CH:14][CH:13]=3)=[CH:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@H](CC(=O)O)c1ccc(OCC2=CC3(CCCC3)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
To a solution of (R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (23.5 g) obtained in Step 4 in a mixed solvent of tetrahydrofuran (94 mL)-methanol (94 mL) was added 2N aqueous sodium hydroxide solution (48 mL), followed by stirring the mixture at room temperature overnight. To the reaction mixture was added 2N aqueous hydrochloric acid solution (48 mL), followed by extraction with n-hexane twice. The organic layers were combined, washed with saturated brine, dried and concentrated to give (R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (26 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[C-:22]#[N:23].[K+].C1OCCOCCOCCOCCOCCOC1.[OH-].[Na+]>O1CCCC1.C(#N)C.O>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[C:22]#[N:23])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C#N)c12
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (5.89 g, 20.0 mmol), potassium cyanide (2.04 g, 31.3 mmol) and 18-crown-6 (6.96 g, 26.3 mmol) in tetrahydrofuran (90 mL) and acetonitrile (90 mL) was heated under reflux for 8 hours. The solution was allowed to cool to room temperature, and poured into water. The solution was made weakly basic by the addition of a sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give crude crystals. The crude crystals were recrystallized from ethyl acetate to give the title compound (2.86 g, 50% yield).
Reaction SMILES: B(O)(O)O.[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7].[NH3:14]>>[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7].[NH4+:14].[N:5]1[C:12]([NH2:13])=[N:11][C:9]([NH2:10])=[N:8][C:6]=1[NH2:7]
Reactant: N
Agent: Nc1nc(N)nc(N)n1
Agent: OB(O)O
Product: [NH4+]

Procedure:
About 100 parts by weight of a commercial melamine borate powder are added to about 100 parts by weight of concentrated aqueous ammonia containing about 25% ammonia while agitating. The mixture is reacted for 12 hours at ambient temperature and pressure. The melamine borate is hydrolyzed into smaller molecules and the ammonia radical reacts with the oxyacid boron radicals thereby producing an ammonium melamine salt of polyboron oxyacid and polyammonium melamine salt of polyboron oxyacid. It is then dried and pulverized into a fine powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+].C(O)C>O1CCCC1>[Cl:17][C:12]1[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[O:8][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1c(-c2cccnc2Cl)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1onc(-c2cccnc2Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid methyl ester (1.90 g, 0.0075 mol) with aqueous sodium hydroxide (2N, 15.0 mL, 0.03 mol), ethanol (3 mL), and tetrahydrofuran (3 mL). Stir for 4 hours at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 3.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Eluted over silica gel with methanol/dichloromethane allowing for isolation of the desired isoxazole acid as an off white solid (0.98 g, 55%). MS(ES): (M+1)+ 238.97, 240.97 m/z.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br.Br.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2c(c1)nc(NC1CCN(CCNc3ncccn3)CC1)n2Cc1ccc(F)cc1
Yield: 83 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 9.66 parts of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-5-ol trihydrobromide, 5 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 5.2 parts (83%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]amino]-1H-benzimidazol-5-ol; mp. 194.4° C. (compound 64).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[C:7]([C:11]1[O:12][C:13]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:14]=2[N:15]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[C:7]([C:11]1[O:12][C:13]2[C:19]([C:20]([O:22][CH3:1])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:14]=2[N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc2c(Cl)ccc(C(=O)O)c2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc(C(C)(C)C)oc12

Procedure:
Oxalyl chloride (2.6 ml) was added dropwise to a stirred suspension of 2-t-butyl-4-chloro-1,3-benzoxazole-7-carboxylic acid (6.2 g). Dry N,N-dimethylformamide (3 drops) was added and the mixture stirred at reflux for 2 hours and evaporated. Dichloromethane was added and the solution added dropwise to a stirred solution of methanol (dry, 3.0 ml) and triethylamine (dry, 10 ml) in dichloromethane at 0° C. After stirring at ambient temperature for 18 hours, the mixture was washed with hydrochloric acid (2M) water, sodium carbonate (2M), water, then dried magnesium sulphate) and evaporated to give methyl 2-t-butyl-4-chloro-1,3-benzoxazole-7-carboxylate (5.7 g) as a light brown solid, m.p. 130°-131° C.
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[F:18][C:19]1[CH:20]=[C:21]([C:26]#[C:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:22]=[C:23]([F:25])[CH:24]=1.Cl[C:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:26]#[C:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:36]3[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=3)[CH2:33][CH2:34]2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Fc1cc(F)cc(C#CCC2CCNCC2)c1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(CC#Cc3cc(F)cc(F)c3)CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 237, but using Compound 248a instead of Compound 237a and 2-chloro-3-nitro-6-picoline instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 9:1, affording the title product as a yellow oil.