Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6](I)[CH:5]=1.C([Mg]Cl)(C)C.C1COCC1.[Cl:23][C:24]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:24]=2[Cl:23])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(I)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
A dry flask was charged with 4-chloro-3-iodo-benzoic acid methyl ester (5.0 g, 16.9 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (35 mL) was added, and the solution cooled to −40° C.; then isopropylmagnesium chloride (8.85 mL, 2.0 M in diethyl ether, 17.7 mmol) was added slowly over 20 min keeping the temperature below −40° C. On completion of the addition the reaction mixture was stirred at −40° C. for 45 min. A THF solution of ZnCl2 (2.32 g, 17.0 mmol, 0.9 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (3.7 g, 17 mmol) and Cu(OAc)2 (68 mg, 0.34 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:6 as the eluent to give the title compound as yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([O:15][C:16]1[C:17](Cl)=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1)[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>COCCOC>[CH2:3]([O:10][CH2:11][CH:12]1[CH2:13][O:14][C:17]2=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=[C:16]2[O:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC(COCc1ccccc1)Oc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1ccc2c(n1)OCC(COCc1ccccc1)O2
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
To a stirred suspension of sodium hydride (75 mg, 3.1 mmol) in anhydrous 1,2-dimethoxyethane (30 mL) was added a solution of 3-(benzyloxy)-2-(2-chloro-6-(trifluoromethyl)pyridine-3-yloxy)propan-1-ol (1.13 g, 3.1 mmol) in anhydrous 1,2-dimethoxyethane (30 mL), dropwise over 5 minutes. The reaction was heated at reflux for 90 minutes, then allowed to cool. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 20% EtOAc in hexanes) gave the title compound (450 mg, 43%) as an oil. m/z=325.6 (M+1), r.t.=3.46 mins. 1H NMR (400 MHz; CDCl3) 57.36-7.25 (7H, m), 4.62 (2H, d), 4.60-4.53 (1H, m, 4.43 (1H, dd), 4.18 (1H, dd), 3.87 (1H, dd), 3.74 (1H, dd).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[C:23](Br)=[CH:22][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]1=[O:34])=[O:14])([CH3:11])([CH3:10])[CH3:9]>[Cl-].[Zn+2].[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.C(=O)(O)[O-].[Na+]>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[C:23]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][N:21]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:20]1=[O:34])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCn1c(=O)c(Br)cn(Cc2ccccc2)c1=O
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: [Cl-]
Product: CC(C)(C)OC(=O)NCCCn1c(=O)c(-c2ccccc2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of zinc chloride (0.5 M in tetrahydrofuran, 2.3 mL, 1.1 mL) and a solution of phenyllithium (1.8 M in tetrahydrofuran, 3.2 mL, 5.7 mmol) were stirred together at −78° C. under inert atmosphere for 10 min when the reaction was warmed to ambient temperature. Tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.057 mmol) and 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-bromo-1H-pyrimidine-2,4-dione (500 mg, 1.1 mmol) were added and the reaction stirred at ambient temperature 20 h. The reaction mixture was treated with saturated sodium bicarbonate (50 mL) and extracted into ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting mixture was purified by pressurized silica gel chromatography (25-35% ethyl acetate in hexane) to provide 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-phenyl-1H-pyrimidine-2,4-dione.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:27].[Li+].[OH-]>>[CH3:12][C:11]1[CH:10]=[C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])[CH:8]=[C:7]([CH3:27])[C:6]=1[CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: CN(P(=NP(=O)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C)C.[PH3]=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:52]1([OH:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.[CH2:59]([O:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH:60]1[O:62][CH2:61]1.ClC1C=C(Cl)C=C(Cl)C=1>P(N(C)C)(N(C)C)N(C)C>[O:58]([CH2:61][CH:60]([OH:62])[CH2:59][O:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: CN(C)P(=NP(=O)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: Clc1cc(Cl)cc(Cl)c1
Product: OC(COc1ccccc1)COc1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
In a 100 mL pear-shaped flask were precisely weighed 0.579 g of tris[tris(dimethylamino)phosphoranylidene-amino]phosphine oxide ([(Me2N)3P=N]3P=O where Me is methyl, same in the following description) as a phosphine oxide represented by formula (1) which was substantially anhydrous by adequate drying over phosphorous pentoxide in a desiccator in vacuo (1.00 mmol) and 9.88 g of phenol (105 mmol). To the mixture warmed to 90° C. was added dropwise 15.0 g of phenyl glycidyl ether (referred to as "PGE"; same in the following description) (100 mmol) over 10 min. After addition, the mixture was stirred at the same temperature for 5 hours, and cooled to room temperature over about 10 min. A small portion of the reaction mixture was quantitatively analyzed by gas chromatography using 1,3,5-trichlorobenzene as an internal standard, indicating that the starting PGE had been almost completely consumed to form desired 1,3-diphenoxy-2-propanol in a yield of 96% based on PGE. In brief, the reaction almost quantitatively proceeded. The reaction mixture was directly subjected to column chromatography to give 22.5 g of 1,3-diphenoxy-2-propanol as a colorless solid in an isolation yield of 92% whose various analyses gave data identical to a reference standard. The catalyst activity (molar amount of a desired product per one mole of catalyst in a unit time; same in the following description) of tris[tris(dimethylamino)phosphoranylidene-amino]phosphine oxide was 20 mol/mol/h, which was surprisingly about 3, 2 or 1.5 times as large as that given by boron trifluoride, N-methylimidazole or triphenylphosphine in Comparative Example 2, 3 or 4, respectively.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CO.C1COCC1>[Cl:12][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1
Reactant: Cc1cn2c(Cl)c(-c3ccccc3)c(Cl)nc2n1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn2cc(-c3ccccc3)c(Cl)nc2n1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
8.3 g (30 mmol) 5,7-Dichloro-2-methyl-6-phenyl-imidazo[1,2-a]pyrimidine are dissolved in 14.5 mL methanol and 85 mL THF. After addition of 3.4 mL acetic acid 5.8 g (45 mmol) zinc/copper pair are added in portions and the mixture is stirred at rt for four and a half hours. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent has been removed and the residue redissolved in ethyl acetate. After washing twice with brine and drying over Na2SO4, the solvent is evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol) yielding only 260 mg of the desired compound. 2N NaOH is added to the zinc/copper slurry of the reaction until a pH of 8. Afterwards the slurry is treated four times with 300 mL ethyl acetate/methanol (1%) each. The solvent mixture is decanted each time and the extracts are combined. After evaporation of the solvents 3.1 g of the desired product are obtained. Repetition of this process yields additional 2.32 g product. Altogether 74.4% of the desired material have been obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH:7]([CH3:29])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1>ClCCl>[ClH:3].[Cl:5][CH:7]([CH3:29])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(C)O)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(C)Cl)CC1
Reaction time: 8 h
Yield: 85 %

Procedure:
14 Parts of sulfinyl chloride are stirred and there is added dropwise a solution of 37 parts of N-[1-(2-hydroxypropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride in 360 parts of dichloromethane. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated and the residue is suspended in 2-propanone. The product is filtered off and dried, yielding 31.5 parts (85%) of N-[1-(2-chloropropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[OH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:25][CH:26]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 2,4-dichloro-bromobenzene (22.6 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 120° C. for 4 hours. After the reaction mixture was cooled, water and benzene were added thereto whereby to form two layers. The organic layer so separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionyl]isoxazolidine (30.9 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 115°-118° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12]O.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][Cl:16]
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1c(CCl)nc([N+](=O)[O-])c1C#N

Procedure:
1.6 G. of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole is dissolved in 25 ml. of benzene and treated with 2.7 ml. of thionyl chloride. The reaction mixture is refluxed for 1 hour, cooled, filtered and evaporated to dryness. The residue is recrystallized from isopropanol affording 0.6 g. of 1-methyl-2-chloromethyl-4-nitro-5-cyanoimidazole.
Reaction SMILES: COC(=O)CCC1C=CC=CC=1.[OH:13][C:14]1[CH:24]=[CH:23][C:17]2[C:18](=[O:22])[CH2:19][CH2:20][O:21][C:16]=2[C:15]=1[CH2:25][CH2:26][CH3:27].C[O:29][C:30](=[O:47])[CH2:31][CH2:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br>>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][O:13][C:14]2[CH:24]=[CH:23][C:17]3[C:18](=[O:22])[CH2:19][CH2:20][O:21][C:16]=3[C:15]=2[CH2:25][CH2:26][CH3:27])=[C:33]([CH2:32][CH2:31][C:30]([OH:47])=[O:29])[CH:38]=1
Reactant: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: COC(=O)CCc1ccccc1
Product: CCCc1c(OCCCCCOc2ccc(Cl)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 70.9 %

Procedure:
Using the procedure of example 4, 5-chloro-2-[5-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester, a pale-yellow oil, was prepared in quantitative yield starting from 0.62 g (3 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 1.21 g (3.33 mmol) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester. Saponification using the procedure of example 4 afforded 1.01 g (71%) of 5-chloro-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as a colorless solid, mp 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2cc(Cl)ccc2OCC1=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(Cl)ccc2OCC1=O

Procedure:
In the same manner as in Reference Example 1, methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was reacted with 3-(4-phenylpiperazin-1-yl)propyl chloride to give methyl 7-chloro-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate. When converted to hydrochloride, white crystals were obtained, melting point 197°-199° C.
Reaction SMILES: [F:1][CH2:2][C:3]([N:19]=CC1C=CC=CC=1)([CH2:8][CH2:9][CH2:10][N:11]=CC1C=CC=CC=1)[C:4]([O:6][CH3:7])=[O:5].[ClH:27]>C(OCC)C>[ClH:27].[ClH:27].[F:1][CH2:2][C:3]([NH2:19])([CH2:8][CH2:9][CH2:10][NH2:11])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CF)(CCCN=Cc1ccccc1)N=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C(N)(CF)CCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 2-fluoromethyl-2,5-bis(benzylideneamino)pentanoate (3.11 g) in diethyl ether (20 ml) and N aqueous HCl (100 ml) is stirred at room temperature for 3 hours. The aqueous phase is decanted, washed with ether, and concentrated in vacuo to give 2.5 g of methyl 2-fluoromethyl-2,5-diaminopentanoate dihydrochloride.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:18]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[CH2:13][C@H:12]([C:14]([O-:16])=[O:15])[C@H:11]([CH3:17])[CH2:10]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)O
Agent: C[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (1240 g, 1499 mmol, prepared using X with Example #24 Step H and dibenzylamine and TT) in THF (8.0 L) was added (R)-(+)-1-phenylethylamine (0.193 L, 1499 mmol). The mixture was warmed to reflux to dissolve the solids, and was then cooled to ambient temperature. After about 15 h, the reaction mixture was filtered, washed THF (800 mL) and dried in a vacuum oven to afford (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate•(R)-1-phenylethanamine (565 g, 85%, 97.5% ee): LC/MS (Table 2, Method 70) Rt=8.49 min. The mother liquor was concd. The residue was dissolved in THF (1 L), heated to dissolve the solids, and cooled to ambient temperature. After about 15 h, the reaction mixture was filtered, washed THF (800 mL) and dried in a vacuum oven to afford additional (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate•(R)-1-phenylethanamine (78.5 g, 12%, 95.2% ee): HPLC (Table 2, Method 70) Rt=8.57 min
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]2[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24][C@@:25]3([CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:26]3)[C:18]=12.[CH3:48][C:49]([CH3:51])=O>ClCCCl.C(Cl)Cl>[CH2:30]([N:27]1[CH2:28][CH2:29][C@:25]2([C:18]3[C:19](=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][NH:15][CH:49]([CH3:51])[CH3:48])[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24]2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3C[C@@]4(CCN(Cc5ccccc5)C4)c4c(CN)cccc43)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)NCc1cccc2c1[C@]1(CCN(Cc3ccccc3)C1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
NaBH(OAc)3 (57.6 mg, 0.272 mmol) was added to a solution of (5R,7R)-4-((S)-4-(aminomethyl)-1′-benzylspiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40 mg, 0.091 mmol), acetone (52.6 mg, 0.906 mmol) in DCE (1.0 mL), and the resulting solution was stirred at ambient temperature for 8 hours. The reaction mixture was diluted with DCM and washed with 25% NaOH. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give (5R,7R)-4-((S)-1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40.0 mg, 0.083 mmol, 91%). LCMS (APCI+) M+H+ 484 (100%); Rt=2.64 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:11]1=[O:27].CC1CC2(CCNCC2)C(=O)N1C1COC(=O)C=1>>[CH3:1][O:2][CH2:3][C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[C:11]1=[O:27]
Reactant: COCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Product: COCC1=C(N2CCC3(CCNCC3)C2=O)COC1=O

Procedure:
The title compound was prepared from tert-butyl 2-(4-(methoxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate in an analogous fashion as described for 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22, last step).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:24][CH:23]=1
Reactant: CSc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(methylsulfanyl)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 411 mg of the title compound (94%) as a yellow solid in 99.3% purity by HPLC (Rt: 5.75, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6]([O:10][CH3:11])([O:8][CH3:9])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][N:21]=[C:22]([NH2:24])[N:23]=1)([O:10][CH3:11])[CH3:7]
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(C)(OC)c1ccnc(N)n1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one (1a) (34.29 g) was dissolved in ethanol (750 mL). Potassium carbonate (65.3 g) and guanidine hydrochloride (20.77 g) were added and the resulting suspension heated to reflux overnight. The reaction mixture was concentrated in vacuo, the residue was stirred with water overnight, filtered and dried in a vacuum oven at 40° C. overnight to afford the title compound (21.01 g) as a white solid. The filtrate was extracted with dichloromethane (3×700 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford a further crop (10.6 g) of the title compound.