Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[C:1]([NH:8][CH2:9][CH:10]([OH:11])[CH:12]=[CH2:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCC=O
Solvent: C1CCOC1
Product: C=CC(O)CNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of dried, powdered 4 A molecular sieves (18 g) and PDC (45 mg, 120 mmol) in 150 mL CH2Cl2 was added a solution of 2-(BOC-amino)ethanol (4.83 g, 30 mmol) in CH2Cl2. The mixture was allowed to stir at ambient temperature for 1.5 hour, then diluted with ether (200 mL) and filtered through a silica gel pad, rinsing throughly with ether. The filtrate was concentrated to afford a clear pale yellow oil (3.46 g, 72%). The aldehyde was used immediately for the next reaction without purification. To a cooled solution of the freshly prepared BOC-Glycinal (410 mg, 2.6 mmol) in 8 mL THF was slowly added 1.0M vinyl magnesium bromide in THF (18 mL) via syringe. The reaction mixture was allowed to stir for 1 hour with warming to -10° C. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and was extracted with chloroform (×4). The extracts were dried and concentrated. The crude oil was purified by flash chromatography on silica gel, eluting with EtOAc/hexane (1/5~1/1, v/v) to give the title compound as a clear pale yellow oil (380 mg, 78% yield). MS(DCI) m/e 205(M+NH4)+. 1H NMR(CDCl3, 300 MHZ) δ1.45 (s, 9H), 2.54 (br s, 1H), 3.10 (dt, 1H), 3.30-3.43 (m, 1H), 4.24 (br s, 1H), 4.92 (br s, 1 H), 5.21 (d, 1H), 5.35 (d, 1H), 5.86 (ddd, 1H). Anal calc for C9H17NO3 : C, 57.72; H, 9.17; N, 7.48. Found: C, 57.85; H, 9.19; N, 7.42.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[H][H]>CC(O)C>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: [H][H]
Reactant: COC1CCCCC1=O
Solvent: CC(C)O
Product: CO[C@@H]1CCCCC1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
Kinetic resolution of racemic 2-methoxycyclohexanone was carried out (see formula (16) below) That is, a reaction was carried out in accordance with the procedures of Example 13 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using 2-methoxycyclohexanone (320 mg; 2.5 mmol) (made by Tokyo Kasei Kogyo Co., Ltd. )as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 1 hours. As a result, (R)-2-methoxycyclohexanone was obtained at isolation yield of 42% (134 mg; 1.05 mmol), (1R, 2S)-2- methoxycyclohexanol was obtained at isolation yield of 50% (164 mg; 1.25 mmol and enantiomeric excess of 91%). GC (column: Chirasil-DEX CB; column temperature:90° C.; injection and detection temperature: 200° C.; helium pressure: 25 kPa; tR of (1R,2S)-2-methoxycyclohexanol: 37.6 minutes(50.8%); tR of 1S, 2S alcohol: 36.5 minutes (2.5%); tR of 2-methoxycyclohexanone:27.0 minutes (46.7%)). enantiomeric excess of (R)-2-methoxycyclohexanone:94% : HPLC (column: CHIRALCEL OB-H; solvent: 200:1 hexane/2-propanol; temperature: 30° C.; UV wavelength: 290 nm; flow rate: 1.0 ml/minute; tR of (R)-2-methoxycyclohexanone: 20.9 minutes (97.2%); tR of Sketone: 17.0 minutes (2.8%). specific rotation of ketone: [α]29D+98.8° (c:2.61; CH2Cl2); absolute structure: R; literature value: [α]22D−112.4° (c:2.08;CH2Cl2),>99%ee(S). specific rotation of alcohol: [α]29D+14.9° (c:1.026; CH2Cl2); absolute structure: 1R, 2S: the absolute structure was determined by HPLC analysis of the product of oxidation of (1R, 2S)-2-methoxycyclohexanol.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:6][CH2:5]1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[O:18]=[C:10]1[C:7]2([CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:19])[F:20])[CH2:5][CH2:6]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one from Step A (3.30 g, 11.6 mmol) in DMF (10 mL) was added sodium hydride (697 mg of a 60% dispersion in mineral oil, 17.4 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min, then tert-butyl bromoacetate (1.88 mL, 12.8 mmol) was added and stirring was continued at room temperature for 72 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, to provide the title compound. MS: m/z=399 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27]([OH:30])[CH:28]=[CH2:29]>>[CH2:27]([O:30][C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1)[CH:28]=[CH2:29]
Reactant: C=CCO
Reactant: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a suspension of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-13A-1a; 30 mg, 0.08 mmol) in allyl alcohol (0.8 ml) was added NaH (60% dispersion in oil, 2 mg, 0.08 mmol). After stirring overnight, the reaction was concentrated and purified on a Chromatotron using methylene chloride as eluant to give product 13A-1 (12 mg, 38%) as a solid: +ESI MS (M+1) 396.4; 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=5.4 Hz, 1H), 7.53–7.40 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 6.68 (d, J=5.4 Hz, 1H), 6.20 (ddt, J=17.0, 10.4, 5.8 Hz, 1H), 5.64–5.58 (m, 1H), 5.45–5.41 (m, 1H), 5.10–5.08 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]>CO.C1COCC1.[Pd]>[NH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC)ccc1N
Reaction time: 8 h

Procedure:
To a mixed solution of methyl 3-ethoxy-4-nitrobenzoate (6.05 g) in methanol (100 ml) and THF (100 ml) was added 10% Pd/C (50% wet, 0.60 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give a crude product (5.21 g) of the title compound. The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:25])[CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])=[C:4]([CH3:25])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccccc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccccc2)c2ccc(Cl)cc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methylphenyl)-1-(2-methyl-pyridin-4-yl)-3-phenylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=365.1 ([M+H]+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:15])[CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N+:23]([C:26]1[CH:33]=[CH:32][C:29](CBr)=[CH:28][CH:27]=1)([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH:13]([OH:15])[CH3:14])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(O)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.6 mmol) in CH2Cl2 is cooled to 0° C. and TFA (2.5 mL) is added dropwise. The mixture is allowed to stir at room temperature overnight. All the volatiles were removed and CH3CN (20 mL) is added. After addition of 4-nitrobenzyl bromide (1.25 g, 5.78 mmol) and K2CO3 (2.0 g, 14.4 mmol), the mixture is stirred at room temperature for 5 hours.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)ncn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ncn4)CC3)ncn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-6-(3,4,5-trimethoxyphenyl)pyrimidine (126 mg) and piperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichlorobenzoyl chloride (5 g, 23.9 mmol) in 50 mL of dichloromethane at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.3 mmol) and pyridine (4.3 mL, 52.6 mmol). The cold bath was removed and the mixture stirred at ambient temperature for 16 hours, diluted with water and extracted with two portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 20% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.61 (d, J=1.9 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 3.60 (s, 3H); 3.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[N:6][CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.C([Br:15])(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:15][C:4]1[CH:3]=[C:2]([CH3:1])[N+:7]([O-:8])=[N:6][CH:5]=1
Reactant: CC(=O)Br
Reactant: Cc1cc([N+](=O)[O-])cn[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(Br)cn[n+]1[O-]

Procedure:
6-Methyl-4-nitro-pyridazine-1-oxide (270 mg, 1.74 mmol) was dissolved in 2 mL acetic acid, acetyl bromide (650 mL, 8.7 mmol) was added and the reaction mixture was heated at reflux for 1 h. The reaction mixture was poured into crushed ice, the mixture was neutralized by addition of sodium hydroxide and extracted three times with dichloromethane (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 80:20→30:70 gradient) and the desired product was obtained as a light brown solid (150 mg, 45%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1O>>[C:1]1([C:13]2([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: CC1CCCCC1O
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
940 g (about 12.0 mole) of benzene was charged into a 3 L 4-necked flask and cooled to below 5° C. in an ice bath, followed by the addition of 1080 g (about 10.5 moles) of 95 concentrated sulfuric acid. The mixture was further cooled until the interior of the reaction vessel was cooled to below 5° C., followed by the addition of a mixture of 550 g (about 4.8 moles) of 2-methylcyclohexanol and 400 g (about 3.8 moles) of benzene in droplets over 5 hours. Thereafter, the reaction was continued for 2 hours. The reaction solution was transferred into a 5 L separatory funnel to separate the sulfuric acid phase. 1 L of pure water was then added to the solution 5 times so as to dissolve and remove the by-products and other impurities. The resulting solution was made alkali with 1% aqueous solution of sodium hydroxide, followed by the addition of 1 L of water until the aqueous phase was made neutral. After the separation of the aqueous phase, the remaining was dehydrated with sodium sulfate anhydride, followed by removal of the light fractions and the excess benzene under at a temperature of 100° C. and pressure of 0.4 kPa (3 mmHg) thereby obtaining about 900 g of crude 1-phenyl-1-methylcyclohexane. This was subjected to vacuum distillation thereby obtaining 800 g of a fraction having a boiling point of 119.7 to 120.5° C. at a pressure of 0.4 kPa (3 mmHg). The fraction was charged into a 2 L autoclave, followed by the addition of 8 g of a nickel-based hydrogenating catalyst. The reaction was carried out at a temperature of 150° C. and at a maximum pressure of 6.86×106 Pa (70 kg/cm2) until the absorption of hydrogen did not occurred. Thereafter, the catalyst was removed thereby obtaining about 820 g of the targeted product represented by the formula
Reaction SMILES: CC(C)([O-])C.[K+].CCOP(OCC)([CH2:12][C:13]#[N:14])=O.[C:18]([O:22][C:23](=[O:33])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23](=[O:33])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=[CH:12][C:13]#[N:14])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CC#N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium tert-butoxide (5.54 g, 49.5 mmol) in dry THF (110 mL) at 0° C., diethyl cyanomethyl phosphonate (8.00 mL, 49.5 mmol) was added slowly dropwise and the mixture was stirred at 0° C. for 1 hour. A solution of trans (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (9.36 g, 41.2 mmol) in dry THF (290 mL) was added slowly over ˜15 mins, then the cooling bath was removed and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic phase was washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum to give 12.6 g (>quant) of trans [4-(2-cyano-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester as a−1:2 mixture of E- and Z-isomers which was contaminated with some phosphonate residues. The golden oil crystallized almost immediately and was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Br-].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14](/[CH:15]=[CH:32]/[C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][N:24]=3)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4-methanesulfonylpiperazin-1-yl)-2-nitrobenzaldehyde (0.36 g, 1.1 mmol) obtained in Step 1 in methanol (5.0 mL), (1H-indazol-3-ylmethyl) triphenylphosphonium bromide (0.54 g, 1.1 mmol) and potassium carbonate (0.31 g, 2.3 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain (E)-3-{2-[4-(4-methanesulfonylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.48 g, 26%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:21]([NH2:29])=[N:22][C:23]([NH2:28])=[N:24][C:25]=3[CH2:26][CH3:27])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[NH2:28][C:23]1[N:22]=[C:21]([NH2:29])[C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)=[C:25]([CH2:26][CH3:27])[N:24]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCN(c3c(N)nc(N)nc3CC)CC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A mixture of 2.0 g (3.85 mmole) of N-[4-[4-(2,4-diamino-6-ethyl-5-pyrimidinyl)-1-piperazinyl]benzoyl]-L-glutamic acid diethyl ester and 0.6 g (7.70 mmole) of a 50% aqueous sodium hydroxide solution in 100 ml of methanol was stirred at room temperature for 16 hours. Methanol was removed in vacuo below 23° C. The residue was dissolved in 50 ml of ice water and filtered. The filtrate was acidified with citric acid to pH 5. The solid precipitate was collected, washed with water, and triturated with boiling ethanol. After drying in vacuo at 67° for 16 hours, 1.3 g of the product was obtained as a white powder; mp 275° C. (with decomposition).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:13][C:14]([C:16]1[C:20]([CH3:21])=[C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[N:18]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:17]=1[CH3:43])=O>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[N:18]([CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[C:17]=2[CH3:43])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C
Reactant: NC1CCCCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)NC2CCCCC2)c(C)n(CC2CCCCC2)c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A solution of 59.5 μl (0.52 mmol) of cyclohexylamine in toluene (2 ml) was treated at RT dropwise with 0.26 μl of a 2 M solution of trimethylaluminum in toluene (0.52 mmol). The reaction solution was stirred 1 h at RT, 200 mg (0.43 mmol) of 5-(3,5-bis-trifluoromethyl-phenyl)-1-cyclohexylmethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester in toluene (2 ml) were added and reaction mixture was heated at 110° C. for 3 h. The mixture was then partitioned between water and ethyl acetate, the organic layer was isolated, dried over sodium sulfate and concentrated in vacuo and purified by column chromatography to give 114 mg of the title compound, MS (ISP) 529.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.C(O/[CH:16]=[C:17](/[C:23](=O)[C:24]([F:27])([F:26])[F:25])\[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]([C:24]([F:27])([F:26])[F:25])=[N:2][NH:3][CH:16]=1)=[O:19])[CH3:22]
Reactant: NN
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 146.66 mmol) in ethanol (500 mL) at −20° C. was added DIPEA (45.3 mL, 266.66 mmol) followed by stirring at this temperature for 10 minutes. Ethyl (2Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (Preparation 113, 32 g, 133.33 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and diluted with EtOAc. The organic solution was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30% EtOAc in hexane to afford the title compound (13 g) that was taken directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[H-].[Na+].[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20]Br)(=[O:15])[CH3:14].O>CN(C=O)C>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OCCOCBr
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOCn1cnc2c(Cl)ncnc21
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-chloropurine (6 g, 38.8 mmoles) in DMF was added sodium hydride 60% (0.93 g) over 1.5 hour period. (2-acetoxyethoxy)methyl bromide was then added at room temperature; the reaction mixture was allowed to stir for 2 hours under Nz atmosphere. H2O was added and the product was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and evaporated in vacuo to give a light yellow solid 7.1 g, 68% yield of 9-[(2-acetoxy-ethoxy)methyl]-6-chloro-purine. The crude was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:18].ClCCl>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Stir a mixture of 2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (2 g, 11.8 mmol), 3-chloroperoxybenzoic acid (77%, 3.1 g, 14.2 mmol) and 3-tert-butyl-4-hydroxy-5-methylsulfide (254 mg, 0.7 mmol) in 1,2-dichloroethane (50 mL) at 85° C. for 4 h under nitrogen. Add extra 3-chloroperoxybenzoic acid (77%, 1.16 g, 4.7 mmol) and stir at 85° C. for 5 h. Allow to cool to room temperature and add dichloromethane (120 mL), wash with 5% aqueous sodium bisulfate, then with saturated aqueous sodium hydrogen carbonate and finally with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:cyclohexane to give 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.55 g, 71%). 1H NMR (400 MHz, CDCl3) δ 3.82 (1H, d, J=13.20 Hz), 3.74 (1H, d, J=12.72 Hz), 3.67 (2H, d, J=3.42 Hz), 3.31 (2H, dd, J=13.45, 5.14 Hz), 1.44 (9H, s).