Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1S(C)(=O)=O.Cl>CC(N(C)C)=O.C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:12]=[C:13]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:14]([C:21]2[CH:22]=[CH:23][C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[N:15][C:16]=1[O:9][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)n1nc(-c2nc(OC3CCCCC3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added cyclohexanol (0.081 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane (60:40 v/v) to give 6-[5-amino-6-(cyclohexyloxy)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (55 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>C(O)C>[Br:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: O
Solvent: CCO
Product: NNc1nc(Cl)ncc1Br

Procedure:
A 500 mL round bottom flask was charged with 5-bromo-2,4-dichloropyrimidine (13.5 g, 59.2 mmol), hydrazine hydrate (8.8 mL, 181 mmol) and absolute ethanol (300 mL). The resulting solution was refluxed under N2 for 12 h. Work-up: the resulting crystalline solid was collected by filtration. The solid was washed with ethanol (100 mL), and dried to afford 17 g (quantitative) of the product as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH2:29]([O:31][CH2:32]OCC)[CH3:30].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:29]([O:31][CH2:32][O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)[CH3:30]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOCOCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
20 g. of cholesterol is dissolved in 300 ml. of formaldehyde diethylacetal, combined under agitation at room temperature with 30 g. of kieselguhr and in incremental portions with 15 g. of phosphorus pentoxide, and agitated for 4 hours at room temperature. The product is filtered off from the insoluble matter, washed with formaldehyde diethylacetal, and the solvent is distilled off under vacuum. The residue is crystallized at 0° C. After adding sodium bicarbonate solution, the crude product is vacuum-filtered, washed with water, and, after drying, 22.5 g. of 3β-ethoxymethoxy-5-cholestene is obtained. The compound, recrystallized from ethyl acetate, melts at 64°-66° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[N:22]=[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]3=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1>[N:19]1[N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:22]=[C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=12
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(OCCn3nc4ccccc4n3)cc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(OCCn2nc3c(n2)CCCC3)cc1
Yield: 67.8 %

Procedure:
5.5 g of 1-benzyloxy-4-[2-(2H-benzotriazol-2-yl)ethoxy]benzene [prepared as described in Example 15(a)] were hydrogenated in a manner analogous to that described in Example 1(b) until no more hydrogen was taken up, whereby 2.8 g (69%) of 4-[2-(4,5,6,7-tetrahydro-2H-benzotriazol-2-yl)ethoxy]phenol having a melting point of 93° C. (from toluene) were obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][Mg]Br>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH3:12]
Reactant: C[Mg]Br
Reactant: O=C(CCCl)c1ccccc1
Product: CC(O)(CCCl)c1ccccc1

Procedure:
4-chloro-2-phenylbutan-2-ol was prepared from 3-chloro-1-phenylpropan-1-one and methylmagnesium bromide following a procedure analogous to that described in Preparation 1 Method 1 Step 2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)CC3)s2)noc1C(F)(F)F
Yield: 78 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxypiperdine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (141 mg, 78%). 1H NMR (CDCl3) 1.58-1.69 (m, 2 H), 1.93-2.00 (m, 2 H), 2.26 (br s, 1 H), 2.37 (s, 3 H), 3.44-3.52 (m, 2 H), 4.00-4.12 (m, 3 H), 7.33 (d, J=4.0, 1 H), 7.46 (d, J=3.5, 1 H). 13C NMR 7.9, 34.4, 42 (br), 66.9, 114.8, 118.7 (q, J=271), 128.0, 129.2, 131.2, 140.1, 155.2 (q, J=40), 158.1, 162.8. 19F NMR −63.1. LC/MS 5.71 min, [M+1]+ 361.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[N:16]=[C:15]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=2)(O)[CH3:18])[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:11]1[N:16]=[C:15]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=2)([F:7])[CH3:18])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(O)(c1cccc(Br)n1)c1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(F)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
117.3 ml (888 mmol) of DAST were added dropwise over the course of 30 min. to a solution, cooled to 10° C., of 105.9 g (296 mmol) of 1,1-bis(6-bromo-2-pyridyl)ethan-1-ol in 1500 ml of chloroform at such a rate that the temperature did not exceed 20° C. The reaction mixture was stirred at 20° C. for 1 h and then hydrolysed dropwise with 500 ml of ice-water (care: highly exothermic reaction) with ice cooling and subsequently with 1000 ml of aqueous 3M NaOH. The organic phase was separated off, the aqueous phase was extracted twice with 100 ml of chloroform, and the combined organic phases were washed once with 500 ml of water and dried over calcium chloride. After the desiccant had been filtered off, the brown organic phase was concentrated to 200 ml and filtered through a silica-gel column. The yellow solution obtained in this way was evaporated to dryness, and the yellow, viscous oil remaining was recrystallised from 200 ml of n-heptane, giving 78.6 g (218 mmol) of the product, corresponding to a yield of 73.7%, in the form of colourless crystal needles—purity according to 1H-NMR>99.0%.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[S:25]([C:29]1[S:30][C:31]([C:34](O)=O)=[CH:32][CH:33]=1)(=[O:28])(=[O:27])[NH2:26]>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:34]([C:31]3[S:30][C:29]([S:25]([NH2:26])(=[O:28])=[O:27])=[CH:33][CH:32]=3)[O:1][N:2]=2)[N:10]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)s1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [CAS-No. 7353-87-9] (0.104 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.12 g, 46%). MS (ISN) 520.1 [(M−H)−]; mp 258.5° C.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].BrBr.[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>CO>[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:3][C:1]#[N:2]
Reactant: Cn1cccc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: Cn1cccc1SC#N
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 93.6 %

Procedure:
Under nitrogen atmosphere, to a mixture of 25 g of KSCN in 60 ml of dry methanol at -78° C. was added 20 g of Br2 dissolved in 45 ml of methanol. The resulting yellow solution was stirred for 5-10 minutes and 10.1 g of 1-methylpyrrole added in one portion. The mixture was allowed to warm to room temperature and stirred for an additional hour. The mixture was poured into 600 ml of ice-water and extracted twice with 200 ml of methylene chloride. The methylene chloride layer was washed, dried and then concentrated to yield 16.1 g of light yellow oil that turns reddish upon standing.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:4]
Reactant: NC1COc2ccccc2C1=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1COc2ccccc2C1=O
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Chloroacetyl chloride (41.6 g, 368 mmol) was added to a solution of 3-amino-chroman-4-one hydrochloride (67 g, 335 mmol) and triethylamine (102 g, 1.01 mol) in tetrahydrofuran (700 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (22.6 g, 94.3 mmol, 28%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].[Br:17]Br>CC(O)=O>[Br:17][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: BrBr
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (0.67 g, 3.1 mmol) in AcOH (5.7 mL) was added a solution of bromine (0.52 g, 3.24 mmol) in AcOH (10.8 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and concentrated under reduced pressure to afford 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one as a yellow solid (1.07 g, crude): 1H NMR (500 MHz, MeOD) δ 7.64 (d, J=8 Hz, 1H), 7.35-7.30 (m, 1H), 7.05-6.90 (m, 3H), 6.20 (d, J=8 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>CCN(CC)CC>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](O)COCc1ccccc1
Yield: 89.2 %

Procedure:
In a 100 ml autoclave were charged 20.0 g (84.7 mmol) of ethyl 4-benzyloxy-3-oxobutyrate, 16 ml of ethanol, and 31 mg (0.034 mmol) of Ru2Cl4((R)-Tol-BINAP)2.NEt3, and asymmetric hydrogenation was performed at 100° C. under a hydrogen pressure of 10 torr for 3 hours (conversion: 100%). The solvent was evaporated under reduced pressure to give 18.0 g of the title compound as liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:53][C:54]([NH2:56])=[NH:55]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:55][C:54]([NH2:56])=[NH:53])=[O:26])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(=N)N)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). After stirring for 30 minutes, guanidine carbonate (0.19 g, 1.05 mmol) was added, and the reaction was heated to 100° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification was achieved by preparative HPLC on a Primesphere 5 C18 (0.2×15 cm) column using a solvent gradient from 55:45:0.1 to 90:10:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.25 g of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:41]=[CH:40][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:6]=1.[C:42](OC1C=CC=CC=1)(=[O:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[C:42]([N:2]=[N:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:31](=[O:39])[N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:20]([CH:30]=2)[O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:40][CH:41]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C=NN)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(CN=NC(C)=O)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 0.85 g (1.4 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride in 10 ml of methylene chloride is added 0.39 g (2.8 mmol) of phenyl acetate and 1 ml of triethylamine. The mixture is stirred at room temperature for 2 days and then poured onto a silica gel column and eluted with 80% ethyl acetate/hexane, and then pure ethyl acetate to give ethyl 5-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a foam; CHN calculated for C33H47N3O7.0.5H2O:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH3:14][NH2:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:15][CH3:14]
Reactant: CN
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Solvent: C1CCOC1
Product: CNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: -15 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution comprising 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinoyl chloride in about 170 milliliters of THF, prepared in accordance with Example 1, was cooled to -15° C. and a saturated excess of gaseous methylamine was introduced to the solution through a bubbler tube in accord with the process of Example 2. The vessel and contents were warmed to about 4° C. and the saturated solution was allowed to sit overnight without stirring at that temperature. The resulting slurry was filtered and the filtrate was concentrated by rotary evaporation at room temperature. The thus concentrated filtrate was vacuum distilled at 94° C. and 0.14 millimeters of mercury providing a 75% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-methylphosphinic amide. NMR and aziridinyl titration characterization of the product indicated a purity of 98.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.Cl.CN>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:31][CH3:29])=[O:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Agent: CN
Agent: Cl
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzoic acid (Example 69, 40 mg, 0.1 mmol) in 1-methyl-2-pyrrolidinone (0.3 mL) was added 1,1′-carbonyldiimidazole (19.5 mg, 0.12 mmol). After stirring for 30 minutes, methylamine hydrochloride (8.1 mg, 0.12 mmol) was added and the reaction stirred for 4 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10% ethanol/ethyl acetate, to give the title compound. δH (500 MHz, d6 DMSO): 8.63 (1H, d, J=4.5 Hz), 8.04–7.94 (6H, m), 7.88–7.82 (3H, m), 7.42–7.34 (2H, m), 7.32–7.26 (1H, m), 7.14 (1H, td, J=1.9, 8.4 Hz), 2.76 (3H, d, J=4.5 Hz); m/z (ES+) 414 [MH+].
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[C:17](#N)C.C[Si](I)(C)C>C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: CC#N
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Product: CN1Cc2ccccc2C(N)C1=O
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 ML of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[C:10](=[O:19])[NH:11][C:12]3[C:17]=2[C:16]=1[C:15]([F:18])=[CH:14][CH:13]=3.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:15]1[C:16]2[C:17]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]=3[C:8]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3][NH:2][C:25](=[O:27])[CH3:26]
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt (from Example 10 above) (35.5 mg, 0.1 mmol) in CH2Cl2 (2 mL) were added acetic anhydride (Fisher Scientific, 10.2 mg, 0.1 mmol) and triethylamine (Aldrich, 20.2 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 2 hours at the same temperature and then quenched with a saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give N-[2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylamino]-ethyl]-acetamide as a brown solid. (Yield 13.5 mg, 38.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-nitrophthalimide (1 g, 5.20 mmol) in dry DMF (35 ml), cooled in an ice bath, NaH (60% w/w dispersion in mineral oil, 0.250 g, 6.25 mmol) was added, followed after 15 minutes by t-butyl bromoacetate (0.845 ml, 5.73 mmol). After stirring for 1 hour at room temperature, the mixture was poured into water and the resulting precipitate was washed with water and with a little amount of Et2O; after drying, tert-butyl 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetate was obtained (1.44 g, 4.70 mmol, 90% yield, MS/ESI+ 328.9 [MNa]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C(OCC)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:20])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1CCOCC1

Procedure:
As per the present invention, the ketoreductase enzyme is dissolved in buffer and to this a solution of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione in an alcohol solvent such as methanol is added at a temperature of 20-40° C. for 15-40 hours and monitored by HPLC. To this immiscible organic solvent such as ethyl acetate is added and (S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one is isolated from organic phase.