Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:14](=[O:17])[C:15]=2[CH3:16])=[CH:6][CH:5]=1.[CH2:30](I)[CH2:31][CH3:32]>CS(C)=O>[CH3:16][C:15]1[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:30][CH2:31][CH3:32])=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To 50 ml of a suspension of 0.36 g (0.018 mole) of sodium hydride in DMSO, 1.7 g (0.0048 mole) of 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone was added, followed by further dropwise addition of 1.0 g (0.0058 mole) of propyl iodide. The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was thereafter poured into ice water, followed by extraction with chloroform. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, followed by recrystallization from a 2:1 mixed solvent of acetone and hexane to obtain 1.6 g of 3-methyl-1,6-diphenyl-2-(4-propoxyphenyl)-4(1H)-pyridinone having a melting point of 165°-168° C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:16][C@@H:15]2[C@@H:11]([CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[CH2:10]1)C1C=CC=CC=1.N#N>CO.CCOC(C)=O.[Pd]>[ClH:1].[CH2:12]1[CH:11]2[CH2:10][NH:9][CH2:16][CH:15]2[CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(Cc3ccccc3)C[C@H]2C1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of 3-benzyl-7-(tert-butoxycarbonyl)-3,7-diazabicyclo[3.3.0]-octane hydrochloride (91.1 g, 269 mmol; from step (d) above) in methanol (250 mL) under a N2 atmosphere there was added 10% Pd/C (w/w; 9.8 g). The N2 atmosphere was exchanged for H2 (1 atm of pressure) and the reaction was stirred for 18 h. The reaction was filtered through a pad of cellulose to remove the catalyst. The filtrate was concentrated in vacuo to afford an off-white solid. The solid was slurried in EtOAc and collected. After drying in a vacuum oven for 18 h at 60° C./66.5 Pa (0.5 mm Hg) there was obtained 58.0 g (87%) of the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([O:30]C)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a mixture of methyl 1-tert-butoxycarbon-vl-4(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (500 mg), methanol (3 ml) and water (3 ml) is added sodium hydroxide (100 mg), which is stirred for 30 minutes at room temperature. The reaction mixture is poured into a 5% aqueous solution of citric acid, followed by extraction with dichloromethane. The organic layer is dried and then concentrated to give a crude product, which is recrystallized from ethyl acetate to afford 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxy-benzoyl)piperazine-2-carboxylic acid (400 mg) as colorless crystals, m.p. 188-190° C.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate in absolute ethanol (500 mL) and potassium carbonate (18 g, 0.13 mol) was stirred for 3 h at 60° C. The mixture was diluted with 500 mL of dichloromethane and the suspension was filtered. The precipitate was washed with 200 mL of dichloromethane. The combined solutions was washed with 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The crude product introduced into a silica gel column and eluted with hexane/ethyl acetate mixture (2:1) to give 20 g (91 mmol, 95%) of desired compound as a yellow solid. 1HNMR (DMSO d-6): 1.30 (t, 3H), 2.45 (s, 3H), 4.30 (qt, 2H), 6.65 (s, 1H), 7.28 (2, 1H) 7.53 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[CH:12]([O:13][CH2:14][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:1]2)=[CH:4][CH:5]=1)=[CH2:11]
Reactant: C#Cc1ccc(O)cc1
Reactant: C1CCOC1
Product: C=COCCOc1ccc(C2CCCCC2)cc1

Procedure:
In 80 ml of THF were dissolved 20 g of poly(p-hydroxystyrene), VP-8000 (produced by Nippon Soda Co., Ltd.), and 6.5 g of 4-cyclohexylphenoxyethyl vinyl ether. Thereto, 0.01 g of p-toluenesulfonic acid was added. The resulting mixture underwent reaction for 18 hours at room temperature. The reaction solution was dripped into 5L of distilled water with vigorous stirring, and fine solid particles precipitated out were filtered off and dried. Thus, Polymer (B-32) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH2:6][CH3:7])[C:4]#[CH:5].C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][C:3]([NH:2][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)([CH2:6][CH3:7])[C:4]#[CH:5]
Reactant: C#CC(C)(N)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(C)(CC)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 4 grams (g) (0.03 mole) of 3-amino-3-methyl-1-pentyne hydrochloride (4 grams (g) (0.03 mole) suspended in 100 milliliters (mL) of methylene chloride in a three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer. Triethylamine (6.82 g, 9.4 mL) was added slowly, keeping the temperature between 5° C. and 10° C. 4-nitrobenzoyl chloride 5 g (0.027 mole) was added to the resulting mixture at a rate to keep the reaction temperature between 5° C. and 10° C. After the addition was complete the reaction mixture was stirred at room temperature for 0.5 hours, and was then sequentially washed with water (2×100 mL), 5% aqueous hydrochloric acid, (2×100 mL), water (1×50 mL), 5% aqueous sodium hydroxide (2×100 mL) and finally with water (1×100 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed in the rotary evaporator, yielding N-(3-methylpent-1-yn-3-yl)-4-nitrobenzamide, used as such in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Reaction time: 0.58 h
Yield: 81.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. 1-Propanesulfonyl chloride (0.184 mL, 1.64 mmol) was added. The solid immediately dissolved. The mixture was stirred 35 minutes, and then it was diluted with dichloromethane and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (628.3 mg, 1.33 mmol, 81%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[NH:38]N>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[N:38]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=482.2 (M+H)+
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:17][C:43](=[O:44])[C:42]([S:41][CH2:40][CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:46]([OH:47])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCC2CCCCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCC3CCCCC3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(cyclohexylmethoxy) acetophenone (2.50 g, 10.77 mmol), lithium bis(trimethylsilyl)amide (2.70 g, 16.16 mmol), chlorotrimethylsilane (2.05 mL,16.16 mmol), THF (107 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ1.15 (m, 5 H), 1.81 (m, 6 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.85 (d, 2 H), 6.67 (s, 1 H), 7.21 (m, 5 H), 7.45 (q, 1 H), 7.74 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2cccc(Cl)c2)(c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (15 drops) is added to a solution of 4,4-bis-(3-chlorophenyl)-cyclohexenone (26.8 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (33 cc) in dry dichloromethane (200 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after having allowed the temperature to return to 25° C. and for a further 15 minutes after addition of potassium carbonate (16 g). After filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 7 cm, height 40 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting 500 cc fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone (16.2 g) in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][O:10][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-1-(3-Chloro-phenyl)-ethane-1,2-diol (9.83 g, 0.057 mol) and triethylamine (11.8 ml, 0.086 mol) a solution of TsCl (10.87 g, 0.057 mol) in dichloromethane (50 mL) was added at 0° C. over 30 min. The mixture was stirred at 0° C. for 4 h. Precipitate formed was removed by filtration, the filtrate was washed with water (50 mL), dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (200 mL), filtered through a SiO2 pad and evaporated. Colorless oil, 16.34 g (0.050 mol, 88%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([O:26][CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#CCO[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCO[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans [4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyloxy]-acetonitrile (350 mg, 770 μmol) in a mixture of ethanol (2.5 mL) and water (800 μL) was treated with ammonium chloride (250 mg, 4.60 mmol) and iron powder (170 mg, 3.10 mmol) and heated at 80° C. for 90 minutes. The reaction mixture was hot filtered through Celite® washing several times with ethanol/water. The filtrate was concentrated under vacuum, the residue diluted with water and extracted in to DCM (3×). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The iron filter cake was stirred in 20% methanol in DCM, filtered and repeated until no further product was extracted. The combined filtrates were washed with water and the phases separated. The aqueous phase was extracted with DCM (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated under vacuum and combined with the material isolated above to afford 300 mg (91%) of trans [4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyloxy]-acetonitrile as a yellow solid. LCMS (Method Q, ESI): RT=2.76 min, m+H=426.1; 1H NMR (400 MHz, CDCl3) δ: 8.14 (m, 2H), 7.83 (s, 1H), 7.53 (t, 1H), 7.49 (d, 1H), 7.45 (t, 2H), 6.52 (d, 1H), 4.72 (d, 1H), 4.30 (s, 2H), 3.73 (m, 1H), 3.58 (m, 1H), 2.80 (br s, 2H), 2.16 (m, 4H), 1.48 (m, 2H), 1.33 (m, 2H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:25][C:26]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1)=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:39][C:38]1[CH:37]=[CH:36][C:24]([CH2:25][C:26]2([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:28][CH2:27]2)=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC([C@H](N)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Reaction time: 8 h

Procedure:
5.31 g (9.61 mmol) of tert-butyl 1-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorobenzyl]cyclopropanecarboxylate (Example 32A, racemic diastereomer mixture) were dissolved in a mixture of 100 ml of ethanol and 20 ml of THF. The solution was inertized with argon, and 511 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with ethanol/THF, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→4:1) and the diastereomers were separated:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14](C(F)(F)F)([C:18]([F:21])([F:20])[F:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][N:31](C)[CH:32]=O>>[CH3:30][N:31]([CH3:32])[C:15](=[O:16])[CH:14]([O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: CN(C)C=O
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (2.06 g.) in dimethylformamide (10 ml.) is added dropwise at 0° C. under argon to a stirred suspension of sodium hydride (216 mg. of a 60% dispersion in oil from which the oil has been washed with light petroleum) in dimethylformamide (15 ml.). The mixture is heated at 100° C. for 18 hours, cooled, and evaporated in vacuo. The residue is mixed with water and the solid obtained (1.8 g.) is washed with water and dried, then chromatographed in toluene on a column of silica (60 g.). The column is washed with toluene (900 ml.) until no more material is eluted, and then with ether. The ether is evaporated and the solid (0.4 g.) is crystallised from light petroleum to give (±)-N,N-dimethyl-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoropropionamide, m.p. 103°-107° C. (212 mg.).
Reaction SMILES: C(OC(CCCCCCN1C(CCCCCCCC)C(=O)NC1=O)=O)C.[CH2:27]([N:31]1[C:35](=[O:36])[CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:33]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53]CC)=[O:52])[C:32]1=[O:56])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:31]1[C:35](=[O:36])[CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:33]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[C:32]1=[O:56])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC1C(=O)N(CCCC)C(=O)N1CCCCCCC(=O)OCC
Agent: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Product: CCCCCCCCC1C(=O)N(CCCC)C(=O)N1CCCCCCC(=O)O

Procedure:
By the method of Example 40, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin (see Example 36) was converted into 3-butyl-1-(6-ethoxycarbonylhexyl)-5-octylhydantoin, which was hydrolysed to give 3-butyl-1-(6-carboxyhexyl)-5-octylhydantoin as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[NH:7][N:6]=1)[CH3:4].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C)C=O>[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[N:7]([CH2:22][CH2:23][O:24][CH3:25])[N:6]=1)[CH3:4]
Reactant: CCc1n[nH]c(CC)c1Oc1cccc(C#N)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOC)c(CC)c1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.54 mmol) was added to a solution of the pyrazole from Example 60 (100 mg, 0.41 mmol) and 1-bromo-2-methoxy-ethane (51 μl, 0.54 mmol) in dimethylformamide (1.5 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and was stirred for 4 hours. The reaction was quenched with water and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the organic phase was washed with water (2×10 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of 100% pentane changing to 100% ethyl acetate and finally ethyl acetate:methanol (90:10, by volume) to provide the title compound (66 mg) as a colourless oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([F:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([F:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-fluoro-piperidin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.59 g, 2.26 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4-fluoropiperidine as a pale yellow oil (0.263 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 4.60 (m, 1H); 3.64-3.52 (m, 4H); 3.26-3.18 (m, 1H); 2.45-2.38 (m, 2H); 2.28-2.17 (m, 2H); 1.96-1.81 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([OH:15])=[O:14].FCCO.[CH2:21]([N:24]1[CH2:28][C:27](=[O:29])[N:26]([CH2:30]O)[C:25]1=[O:32])[C:22]#[CH:23]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH2:30][N:26]1[C:27](=[O:29])[CH2:28][N:24]([CH2:21][C:22]#[CH:23])[C:25]1=[O:32])=[O:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCCF
Agent: OCCF
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCCF)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, (1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]cyclopropane-carboxylic acid prepared as in Example 21 except 2-fluoroethanol was used and (3-propargyl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propargyl-2,5-dioxo-1-imidazolidinyl)-methyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+18°±2° (c=1% in CHCl3)