Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl.O>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([N:33]([O:34][CH3:35])[CH3:32])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cis-4-hydroxycyclohexanecarboxylic acid (6 g, 0.042 mol) and EDCI (9.6 g, 0.05 mol, 1.2 eq.) were dissolved in DCM (100 mL) at 0° C. and stirred for 10 min. DIPEA (16 mL, 0.126 mol, 3.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (4.44 g, 0.046 mol, 1.1 eq.) were added to the mixture at 0° C. The mixture was warmed to room temperature and stirred for 15 h., water was added and the mixture was extracted with DCM. The organic layer was concentrated and purified by silica gel column chromatography using DCM/CH3OH (10/1) to give product as a colorless oil (3.685 g, 40%). 1H NMR (400 MHz, CDCl3) δ: 4.01 (s, 1H), 3.70 (s, 3H), 3.18 (s, 3H), 2.72-2.69 (m, 1H), 1.98-1.85 (m, 4H), 1.62-1.55 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:7]([CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[C:7]([CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1CC1=NCCN1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)cc(C)c1Cc1ncc[nH]1
Yield: 87.7 %

Procedure:
A suspension of 2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1H-imidazole (free base of Example 5c) (0.1 g, 0.4 mmol) and 10% Pd-C (0.1 g) in toluene (10 mL) was refluxed under a nitrogen atmosphere for 3 days. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1H-imidazole (0.085 g) as a white solid. The oxalate salt was prepared and recrystallized from MeOH/Et2O to afford the title compound as white crystals (0.088 g, 66%). mp 154-156° C., Anal. C16H22N2 ·C2H2O4 : C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16](O)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].CN(C)C=O.S(Cl)([Cl:31])=O>ClCCl>[OH:19][C:5]1[C:6]([CH2:10][CH:11]=[C:12]([CH3:13])[CH2:14][CH2:15][C:16]([Cl:31])=[O:17])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[C:3]2[C:4]=1[C:20](=[O:21])[O:22][CH2:23]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)Cl)C(=O)OC2

Procedure:
A solution of mycophenolic acid (320 g, 1 mol) and dimethylformamide (0.1 g) in dichloromethane (3.2L) at reflux was treated dropwise with thionyl chloride (82 mL, 1.12 mol). After one hour additional heating at reflux, the volatiles were distilled at reduced pressure leaving a gray solid residue of (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride which was cooled and dissolved in anhydrous tetrahydrofuran (1L).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C([O-])(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), 2-methylpseudourea sulfate (1.72 g, 10.0 mmole), and sodium acetate (1.8 g, 22.0 mmole) in tetrahydrofuran (10 ml) is heated under reflux for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate is washed with sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gives a yellow oil which is purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam is crystallized from isopropyl ether-hexanes to provide 1.53 g of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; m.p. 103.5°-105°. TLC (silica gel; ethyl acetate:hexanes, 50:50) Rf =0.31.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[C:14]1([OH:20])C=CC=C[CH:15]=1.[NH3:21]>[OH-].[K+]>[C:14]([NH:21][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1)(=[O:20])[CH3:15]
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: N
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1cc(C)c2cc(C)ccc2n1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-4,6-dimethylquinoline (3.8 g, prepared as described in note q above) and phenol (14 g) was heated to 140° C. and dry ammonia gas was passed into the stirred mixture for 3 hours. After cooling the mixture was dissolved in an aqueous potassium hydroxide solution (10% w/v) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with aqueous N sodium hydroxide solution, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on a silica gel column using a 1:7 v/v mixture of methanol and ethyl acetate as eluent. There was thus obtained 2-amino-4,6-dimethylquinoline (0.4 g). A mixture of this product (0.4 g) and acetic anhydride (10 ml) was stirred at 20° C. for 3 hours and then evaporated to dryness. The residue was washed with petroleum ether (b.p. 60°-80° C., 3×25 ml) to leave 2-acetamido-4,6-dimethylquinoline as a pink solid (0.37 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15]Cl>CN(C)C=O.C(OCC)(=O)C>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15][N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: NC(=O)c1cccnc1N
Reactant: ClCc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cl
Product: N=c1c(C(N)=O)cccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 37.9 %

Procedure:
To a solution of 2-aminonicotinamide (0.18 g) in N,N-dimethylformamide (3 ml) was added 3,5-dichlorobenzyl chloride (0.31 g), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (0.10 g).
Reaction SMILES: [CH2:1]([NH:3][CH:4]=[O:5])[CH3:2].[CH3:6][O:7][CH:8](Cl)[CH3:9]>C(N(CC)CC)C>[CH3:6][O:7][CH:8]([N:3]([CH2:1][CH3:2])[CH:4]=[O:5])[CH3:9]
Reactant: CCNC=O
Reactant: COC(C)Cl
Solvent: CCN(CC)CC
Product: CCN(C=O)C(C)OC

Procedure:
8.0 g of triethylamine and then a mixture of 42.5 g of triethylamine (0.5 mole in total) and 14.6 g (0.2 mole) of N-ethylformamide are added dropwise, at 0° C., to a mixture of 60 ml of light petroleum and 38 g (0.4 mole) of α-chloroethyl methyl ether.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=O)[C@@H:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(C)C>C1COCC1>[C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[OH:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of (S)—N-((1-adamantyl)methyl)-2-hydroxy-2-phenylacetamide (85 mg, 0.28 mmol) in THF (10 mL) was added BH3.Me2S (10 M, 85 μL, 8.5 mmol) under nitrogen. The mixture was heated under reflux overnight and then cooled to rt. The reaction was quenched with methanol. The mixture was concentrated in vacuum to give crude product, which was purified by preparative TLC to afford (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (40 mg, 50%). 1H NMR (MeOD, 400 MHZ): δ=1.31-2.01 (m, 15H), 2.42 (q, 2H), 2.81 (d, 2H), 4.88 (t, 1H), 7.21-7.43(m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][C:18]#[N:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:23][CH:22]=1.C(N(CC)CC)C.C>CC#N.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[C:29]4[C:21]([CH3:20])=[CH:22][NH:23][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:31][C@@H:32]2[CH3:36])=[N:17][C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 60.1 %

Procedure:
The cyanocarbamimidate from step A (9.48 g, 30 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from Example 1, step B (6.93 g, 30 mmol), and triethylamine (4.16 ml, 30 mmol) were combined in MeCN (250 ml) and heated to 85° C. for 6 hours. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (750 g SiO2, 0-7% MeOH:CH2Cl2) to give a yellow foam. This material was dissolved in MeOH and stirred with activated charcoal at 60° C. for 15 min. The mixture was filtered through celite, washing with copious amounts of MeOH and 10% MeOH:CH2Cl2, and concentrated under vacuum. The residue was purified again by flash chromatography (750 g SiO2, 0-7% MeOH:CH2Cl2). The resulting material was dissolved in MeOH, and water was added to crash out the product. The mixture was concentrated under vacuum, and the product was resuspended in water and lyophilized to give a hydrate of (S)—N-(3-bromophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (8.17 g, 57%, 1.25 eq. H2O based on CHN analysis) as an amorphous white solid.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[C:23]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:24]([C:25](=O)[C:26]#[CH:27])=[C:18]2[CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[C:23]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:24]([C:25]3[CH:26]=[CH:27][N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:18]2[CH:17]=1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium ethoxide (0.7 mL (2.09 mmol), 21% in ethanol) and N-cyclopentyl guanidine hydrochloride (0.47 g, 2.88 mmol) were added sequentially to ethanol (30 mL). The resulting solution was stirred at room temperature for 30 minutes. 1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.5 g9, 1.61 mmol) was added, and the suspension was stirred at room temperature for 2 days. The reaction was quenched by the addition of water. The aqueous phase was extracted by ethyl acetate. The organics were combined, washed with brine and dried over magnesium sulfate. Filtration and concentration gave a solid. This solid was recrystallized from methanol to give 4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.45 g, 66%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.59 (broad s, 1H), 8.42 (d, 1H), 8.05 (d, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 6.91 (dd, 1H), 6.39 (d, 1H), 5.34 (broad s, 1H), 4.42 (m, 1H), 3.92 (s, 3H), 2.17 (m, 2H), 1.86–1.60 (m, 6H); MS m/z 420 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.[ClH:21].Cl[C:23]([O:25][CH2:26][CH2:27]Cl)=[O:24]>>[CH:20]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:23](=[O:24])[O:25][CH:26]([Cl:21])[CH3:27])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Cl
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)OCCCl
Product: CC(Cl)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Yield: 85.8 %

Procedure:
Following the general procedure of Example 50, but using 1.5 g (0.005 mol) of desipramine hydrochloride and 0.86 g (0.006 mol) chloroethyl chloroformate and carrying out the reaction at 5°-10° C. for 2 hours, gave 1.6 g (86%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[NH2:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1.N1C=CC=CC=1>CC(C)=O>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([NH:8][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:11]=2[S:16](=[O:18])(=[O:17])[N:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Ethane sulfonylchloride (75.6 mg, 0.588 mmol) was added carefully dropwise to a solution of Example 39H (70.0 mg, 0.147 mmol) and pyridine (93.1 mg, 1.18 mmol) in acetone (7 mL). The reaction mixture was stirred for 4 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 0-25% ethyl acetate/hexane gradient to give the title compound (74 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42 (m, 1H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3H) 0.80 (m, 1H) 1.22 (t, J=7.35 Hz, 3H) 1.33 (m, 1H) 1.57 (s, 3H) 2.07 (m, 1H) 2.22 (m, 1H) 3.19 (m, 2H) 5.76 (s, 1H) 7.53 (dd, J=7.91, 4.23 Hz, 1H) 7.57 (dd, J=8.82, 2.21 Hz, 1H) 7.63 (d, J=2.21 Hz, 1H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=3.68 Hz, 2H) 8.16 (d, J=7.72 Hz, 1H) 10.31 (s, 1H) 13.77 (s, 1H).). MS (ESI+) m/z 532.0 (M+H)+, 549.1 (M+NH4)+ (ESI−) m/z 530.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:19]#[N:20])([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Yield: 93 %

Procedure:
To a solution consisting of 42.71 gm. (0.139 mole) of the dimethyl ester of 4-(p-fluorophenyl)-4-cyanopimelic acid (prepared in Part A, above) and 900 ml. tetrahydrofuran is added 31.3 gm. (0.28 mole) potassium tert-butoxide. This reaction mixture is heated at the reflux temperature for four and one half (41/2) hours. It is allowed to cool. It is then chilled in ice and 225 ml. of 2.5 N aqueous acetic acid is added. The organic layer that forms is recovered and diluted with 750 ml. benzene. The benzene:tetrahydrofuran solution is washed successively with sodium bicarbonate, with water, and finally with brine. The solvents are then removed by evaporation under reduced pressure to give 35.6 gm. (93% yield) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone as a gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19](Br)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([NH:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:18]([C:22]#[N:23])=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(Br)c2C#N)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(NCc3ccccc3)c2C#N)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-bromo-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.547 mmol) in DMSO were added triethylamine (0.229 mL, 1.341 mmol) and benzylamine (0.147 g, 1.367 mmol). The mixture was stirred at 70° C. for 12 hrs. After cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtrated, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-2/1) to give tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-benzylamino-3-cyano-4-pyridinyl}-1-piperidinecarboxylate as a yellow amorphous. (0.290 g, yield; 92%)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:11])[O:6]CC(C)C>Cl>[NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:6])[OH:11]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN
Agent: Cl
Product: CP(=O)(O)C[C@@H](O)CN
Temperature: 25 °C

Procedure:
A solution of 1.1 g of isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-methyl-phosphinate in 20 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 12 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated four times with 25 ml of water. The crude material is dissolved in water, washed with ether and the aqueous layer is treated with activated charcoal. The solution is filtered hot, the filtrate is concentrated under reduced pressure, the residue dissolved in 20 ml of ethanol and treated with 1 ml of propylene oxide. The mixture is stirred until the precipitated solid is free of halogen. The solid is then filtered and recrystallised from methanol/acetone give P-[3-amino-2(S)-hydroxypropyl]-P-methyl-phosphinic acid, m.p. 221°-222.5°, 31P-NMR spectrum: δ=+38.9 ppm (D2O), [α]D25 =-6.0° (c=0.887% in H2O).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([NH2:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CCOC(C)=O.C1COCC1>[CH2:41]([NH:48][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:19])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCN
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114 B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and heptylamine (50 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (25 mg, 0.052 mmol, 20% yield). 1H NMR (MeOH-d4, 300 MHz) δ ppm 0.87-0.95 (m, 3H), 1.34 (s, 12H), 1.37-1.43 (m, 7H), 1.43-1.51 (m, 6H), 1.58-1.71 (m, 2H), 2.13-2.27 (m, 1H), 2.18 (s, 1H), 3.32-3.37 (m, 2H), 3.40 (t, J=7.1 Hz, 2H), 3.87-3.97 (m, 2H), 4.19 (d, J=7.1 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.6, 1.9 Hz, 1H), 8.16 (s, 1H), 8.77 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 481 (M+H)+; Anal. Calculated for C30H44N2O3.0.2H2O: C, 74.40; H, 9.24; N, 5.78. Found: C, 74.43; H, 9.00; N, 5.81.
Reaction SMILES: [OH:1][CH:2]([C:18]1[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=[CH:21][N:22]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:18]1[NH:22][CH:21]=[CH:20][N:19]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncc[nH]1)CC2
Yield: 71.7 %

Procedure:
A solution of 8,9-dihydro-7-[(hydroxy)(1-trityl-1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (376 mg) in acetic acid (15 ml) and water (5 ml) was stirred at 60° C. for 2.5 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (15% methanol-chloroform), followed by recrystallization from methanol, gave 8,9-dihydro-7-[(hydroxy)(1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (148 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
A slurry of 3-bromophenol 100 g (580 mmol), benzylchloride 80 g (700 mmol), and K2CO3 168 g (1210 mmol) in 2 L of DMF was stirred for sixteen hour at ambient temperature. The reaction mixture was filtered and evaporated to dryness. The solid was partioned between CHCl3 and water. The organic layer was separated, washed twice with brine, and dried by filtration through anhydrous Na2SO4. The solution was evaporated to dryness. This yielded 142.5 g of the title compound as a white solid.