Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[CH:6][N:7]=1)=[O:18]
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reaction time: 16 h
Yield: 75 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (450 mg, 2.0 mmol) and bromo-phenyl-acetic acid (430 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (280 μL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 mg, 2.2 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography using a gradient of 10-30% ethyl acetate in hexanes to yield a pale yellow solid (633 mg, 1.50 mmol, 75.0%). ESI-MS m/z calc. 420.0, found 421.2(M+1)+Retention time 3.63 minutes.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[BH4-].[Na+]>C(B(CC)CC)C.C1COCC1.CO.COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COCCOCCOCCOC
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 130 mmoles) from Step (1) is dissolved in 100 mL 1 M triethylborane in THF and 65 mL tetrahydrofuran, stirred for about 2 hours at room temperature, then cooled to −75° C.±20° C., and diluted with 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme (75 mL) is added slowly. After the addition, the reaction mixture is warmed to 20° C. to 25° C. The reaction mixture is quenched by the addition of 20 mL methanol and 8 g acetic acid and concentrated by vacuum distillation—saving the distillate. The residue is diluted with 100 mL water and 200 mL ethyl acetate, agitated, and the phases separated. The organic layer is concentrated by vacuum distillation—keeping this distillate separate from the first one. The residue is dissolved in 200 mL methanol and 10 mL acetic acid and concentrated by vacuum distillation. The residue is dissolved in 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved in 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R—(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.C(O)(=[O:18])C>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2](=[O:18])[NH:3][N:4]=2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(Oc2ccc(Cl)nn2)cc1
Reactant: CC(=O)O
Product: O=c1ccc(Oc2ccc(Cl)cc2)n[nH]1
Yield: 80 %

Procedure:
A solution of 10 g 3-chloro-6-(4-chlorophenoxy)-pyridazine in 100 ml acetic acid is maintained at reflux temperature for a few hours. The precipitate which appears on cooling is isolated and then recrystallised from butanol. There is thus obtained, at 80% yield, 6-(4-chlorophenoxy)-3-pyridazinone which melts at 202° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C1COCC1.C(OCC)(=O)C>[CH3:7][O:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNc1ccccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Potassium carbonate (4.15 g) and 2-methoxyethylamine (1.3 ml) were added to a solution of 1-fluoro-2-nitrobenzene (1.56 ml) in dry THF (20 ml). The mixture was stirred at 23° for 24 h, then it was diluted with ethyl acetate, washed with a saturated ammonium chloride solution (100 ml), 10% sodium hydroxide solution (100 ml) and brine (100 ml), dried and concentrated in vacuo. The residue was purified by flash chromatography (eluting with CH-EA 3:1) to give the title compound as an orange oil (2.55 g). T.l.c. CH-EA (2:1), Rf 0.51.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:24][C:21]2[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2ncccc2=O)n1
Yield: 36 %

Procedure:
Using the method described in Example 78, Step 3, from 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (As prepared in Example 78, Step 2) and 1-methyl-1H-pyrazol-3-ylamine afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as a white solid (37.1 mg, 36%); ES+-HRMS m/e calcd for C16H21N5O2 [M+H+] 316.1768 found 316.1768. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.07 (br s, 1H), 1.24-1.36 (m, 1H), 1.36-1.49 (m, 2H), 1.49-1.74 (m, 5H), 1.93 (ddd, J=13.4, 8.6, 4.5 Hz, 1H), 2.18-2.31 (m, 1H), 3.73 (s, 3H), 5.51 (dd, J=10.7, 4.7 Hz, 1H), 6.35 (d, J=2.0 Hz, 1H), 6.94 (dd, J=9.5, 1.5 Hz, 1H), 7.42 (dd, J=9.5, 3.7 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.99 (dd, J=3.7, 1.5 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]1([C:18]2([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])(=O)=O>O1CCCC1.O>[CH3:36][N:35]([CH2:34][CH2:33][C:19]1[C:18]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=1)[CH3:37]
Reactant: C1=CC(C2CCCCC2)(C2CCCCC2)C=C1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC1=CC=CC1(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (18.7 mL; 1.6 mol/L; 30 mmol) was added dropwise to a cooled (0° C.) solution of dicyclohexyl-cyclopentadiene (Example IV) (6.90 g; 30.0 mmol) in dry tetrahydrofuran (125 ml) in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, 30.0 mmol of 2-dimethylaminoethyl tosylate prepared in situ were added. After 18 hours of stirring, the conversion was found to be 88%, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and evaporated to dryness. The residue was purified on a silica gel column, which resulted in 7.4 g of (dimethylaminoethyl)dicyclohexylcyclo-pentadiene.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].COC(OC)[N:14]([CH3:16])C.O.[NH2:20]N>>[CH3:1][CH:2]([C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:16][NH:14][N:20]=1)[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: COC(=O)CC(=O)C(C)C
Solvent: O
Product: COC(=O)c1c[nH]nc1C(C)C

Procedure:
Using methyl 4-methyl-3-oxopentanoate (2.9 g), dimethylformamide dimethylacetal (2.8 mL) and hydrazine monohydrate (1.1 mL) and in the same manner as in Example 1(3), a crude product of methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate was obtained. This was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2-chloro-5-trifluoromethylpyridine (3.6 g) were added, and the mixture was stirred at 100° C. for 2 hr. In the same manner as in an Example 1(4), the title object compound (4.6 g, 73%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9](C=O)=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24].[C:48]1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:48]=[CH:28][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:8]2[CH3:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)c(C=O)c(C)n2Cc1ccc(Br)cc1
Reactant: Cc1ccccc1
Product: CCOC(=O)C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12

Procedure:
A mixture of the indole from Step 2 (8.46 g, 23.6 mmol) and (carbethoxymethylene)triphenylphosphorane (16.9 g, 48.6 mmol) was suspended in 25 mL of toluene and heated to reflux for 15 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (25% ethyl acetate/hexanes) to provide 9.38 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][C:24]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(S(N)(=O)=O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 90 °C

Procedure:
A 50-mL flask under argon were added 6-bromo-1-morpholinophthalazine (150 mg, 0.51 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (227 mg, 0.76 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), ethyl alcohol (1 mL), and 1,2-dimethoxyethane (4 mL), followed by 2M potassium carbonate aqueous solution (0.77 mL, 1.53 mmol). The reaction was heated at 90° C. for 2 h. The cooled reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine; dried (MgSO4) and concentrated in vacuo. Trituration of the resulting crude solid with CH2Cl2 afforded a pure batch of the title compound as a white solid. Found MS (ES+): 385.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13]O2.[CH3:30][NH2:31]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:31]([CH3:30])[CH:13]=[CH:14][N:15]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][N:25]=2)[N:22]=1
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccn2c(-c3ccc4nnc(C(C)(C)O)n4n3)c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
The 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.200 g, 0.505 mmol, Example #35) in 1,4-dioxane (1 mL) and 40% methylamine in water (1.5 mL, 17 mmol) was heated in a CEM microwave at about 120° C. for about 55 minutes, (100 psi maximum pressure, 5 min ramp, 300 max watts). The mixture was evaporated and then dissolved in HOAc (2 mL). The solution was stirred at room temperature for about 1 hour then the material was purified by RP-HPLC (Table 1, Method f). The combined fractions were concentrated under reduced pressure to remove the acetonitrile then the solution was basified with saturated aqueous NaHCO3 solution gave an oil. The mixture was extracted with 20% EtOAc in DCM (25 mL) then EtOAc (approx. 15 mL). The combined organics solutions were dried over MgSO4 then filtered and evaporated. The solid was triturated with about 10 mL water then collected by filtration. The material was dissolved in hot acetonitrile (1 mL) then added dropwise to about 10 mL water. The solution was allowed to stand at ambient temperature until a solid formed then the mixture was diluted with water (5 mL). The solid was collected by filtration then dried under vacuum at about 80° C. to give the title compound (0.040 g, 20%); 1H NMR (DMSO-d6) δ 8.15 (d, 1H), 8.10 (d, 1H), 7.76-7.67 (m, 1H), 7.46 (m, 2H), 7.31-7.23 (m, 1H), 6.85-6.80 (m, 1H), 5.66 (s, 1H), 3.72 (s, 3H), 1.78 (s, 6H); LC/MS (Table 1, Method g) Rt=1.65 min; MS m/z: 410.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CN(C)C1C=CC=CC=1.Cl>C(OCCCC)(=O)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: N#C[C@@H](O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CCCCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
(s)-2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in butyl acetate (100 mL) in a suitable reaction flask. N,N-dimethyl aniline (10 mL) was added dropwise to the mixture at 0-5° C. and the reaction continued at 20-25° C. for 3 hours, and then refluxed till the reaction was completed by TLC monitoring. Cold down the reaction mixture, 5% HCl (50 mL) was added and stirred at room temperature. Butyl acetate layer was separated and washed with water (50 ml×2). After removal of the solvent under reduced pressure, the target product was obtained (31 g, yield 96.9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Br:13][CH2:14][C:15](Br)=[O:16]>C(Cl)Cl.O>[Br:13][CH2:14][C:15]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[O:9][CH3:10])=[O:16]
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) solution of 5-chloro-2,4-dimethoxyaniline (5 g) in DCM under an atmosphere of argon is treated dropwise with bromoacetyl bromide (2.4 ml). After 5 minutes, TEA (7.5 ml) is added dropwise and after stirring for 20 minutes the reaction mixture is diluted with water and extracted with DCM). The organic phase is washed with distilled water, dried over Na2SO4, filtered and evaporated to give a beige solid. This is purified by flash column chromatography on silica, eluting with 20-100% n-hexane in DCM to afford the title compound. [M+H]+ 308.
Reaction SMILES: CO[C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=O.[CH3:64]OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:3][N:5]([CH3:64])[CH:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)C(c5ccccc5)N(C)C)[nH]3)cc2CO4)[nH]1)C(C)C

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amide coupling. LCMS-ESI+: calculated for C48H52N8O5: 820.41; observed [M+1]+: 821.25.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:26]([O:28][CH3:29])=[O:27])([N:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[CH3:29][O:28][C:26]([C:11]1([N:14]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:27]
Reactant: COC(=O)C1(N(OCc2ccccc2)C(C)=O)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1(N(OCc2ccccc2)C(C)=O)CCNCC1

Procedure:
A mixture of 12.45 g of 1-benzyl-4-methoxycarbonyl-4-(N-phenylmethoxyacetamido)piperidine and 250 ml of acetic acid is hydrogenated at room temperature and pressure with 1.5 g of 10% palladium-on-charcoal catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off. The acetic acid is flash evaporated, the residue is dissolved in toulene and stirred with 10 g of anhydrous sodium carbonate. The solid is filtered and the filtrate is flash evaporated to obtain 4-methoxycarbonyl-4-(N-phenylmethoxyacetamido)piperidine.
Reaction SMILES: [BrH:1].[N+](=[CH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N-]>>[Br:1][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)CCc1ccccc1
Product: O=C(CBr)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0° C. solution of the crude product from Step A (12.89 grams; dry dichloromethane; 150 mL) was treated dropwise with 48% HBr (36.0 mL). When outgassing ceased, the solution was warmed to ambient temperature. After 15 minutes, the reaction was partitioned (isopropyl acetate and water), washed twice with water and dried (magnesium sulfate). Filtration and evaporation furnished the title compound as an oil which crystallized on standing,
Reaction SMILES: C([NH2:4])(=[O:3])C.[OH:5][P:6]([OH:8])[OH:7].[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10].O.C(O)(=O)C=O.C1OC1C>CO>[OH2:3].[NH2:4][O:5][P:6]([CH2:10][C:9]([OH:12])=[O:11])([OH:8])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)=O
Reactant: OP(O)O
Agent: CC1CO1
Agent: O=CC(=O)O
Solvent: CO
Solvent: O
Product: NOP(=O)(O)CC(=O)O
Temperature: 45 °C

Procedure:
A solution of 11.8 parts by weight of acetamide, 16.4 parts by weight of orthophosphorus acid in 40 parts by volume of acetic anhydride are heated with stirring to 45° C. To this solution is added, portionwise, 22.2 parts by weight of glyoxylic acid hydrate over 15 minutes. The reaction temperature increases to 80° C., during the addition and this temperature is maintained by external heating for a further 3 hours. The acetic anhydride is removed by distillation, in vacuo, and the viscous residue dissolved in 100 parts by volume concentrated hydrochloric acid. This solution is heated to reflux for 4 hours, then evaporated to dryness to give a brown crystalline solid, which on dissolution in 600 parts by volume of 60% aqueous methanol, followed by addition of propylene oxide, gives 9.3 parts by weight of 2-aminophosphono-acetic acid monohydrate melting at 195° C. with decomposition and having the following elemental analysis by weight:
Reaction SMILES: [NH2-:1].[Na+].[C:3](O)(=O)CCCCCCC/C=C\CCCCCCCC.CO[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1>[CH3:3][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[NH2:1][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][N:27]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: [NH2-]
Reactant: COc1cccnc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccnc1
Product: Nc1ccccn1
Temperature: 120 °C

Procedure:
A mixture of 28.1 g (0.72 mole) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid, and 65.5 g (0.60 mole) of 3-methoxypyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 340 psig. Cooling water was turned on the reflux condenser. The mixture was heated with stirring to 120° C. and kept heating (maximum temperature 136° C.) for about 4.5 hours until noncondensable gases stopped passing through the pressure relief valve. The autoclave was cooled the 25° C., vented to atmospheric pressure, and hydrolyzed with 150 cc of water. The oil phase was separated. The aqueous phase was extracted twice with 50 cc of an equal volume solution of 4-picoline and toluene. The oil layer and extracts were combined and distilled under vacuum to give 0.14 mole of recovered 3-methypyridine, 0.05 moles of 2-aminopyridine. 0.02 moles of 3-aminopyridine, 0.02 moles of 2-amino-3-methylpyridine, and 0.18 moles of 3-hydroxypyridine. When 3-methoxypyridine was aminated with sodamide in refluxing xylene at atmospheric pressure, a 40.3% yield of 2-amino-3-methoxypyridine (m.p. 79°-80° C.) was obtained. Both 2-amino-3-methylpyridine and 2-amino-3-methoxypyridine are valuable as starting materials for preparing herbicides as shown in Suzuki et al., Ger. Offen. 2,831,578 (1979). The 3-hydroxypyridine is a valuable starting material for the preparation of the drugs pirbuterol (cardiostimulant and oral brochodialator) and pyridostigmine (cholinergic).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH3:12]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)c1cccs1
Agent: Cl
Product: CC(=NNc1ccc(F)cc1)c1cccs1

Procedure:
This compound is prepared from commercial 4-fluorophenylhydrazine hydrochloride (Aldrich) and from commercial 2-acetylthiophene (Aldrich), according to the procedure 1.