Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(t-butoxycarbonyl)azetidine-3-carboxylic acid (1-1) (AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 mL)/Toluene (20 mL) and then cooled to 0° C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started clear and slowly turned yellow. The solution was stirred for 10 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-t-butyl 3-methyl azetidine-1,3-dicarboxylate (1-2) that was used directly in the next step without being purified (99% crude yield).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C=O.[C:17](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:17][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,4S)-tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g, 12.6 mmol, Eq: 1.00) was dissolved in 126 ml of methanol. Formaldehyde (23.5 ml of a 37% aqueous solution) and acetic acid (2.17 ml) were added. Sodium triacetoxyborohydride (4.01 g, 18.9 mmol, Eq: 1.50) was added in portions. The reaction was stirred at room temperature overnight. The reaction was concentrated on a rotary evaporator. DCM and sodium bicarbonate were added to the residue and the layers were separated. The organic layer was washed with dilute bicarbonate, concentrated, and used without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[O:8]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42].Cl>C(Cl)Cl>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[C:9]1[O:8][C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCCCC1(c2ccccc2)OC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride, prepared as in the above examples, (50 mg, 0.11 mmol) in anhydrous CH2Cl2 (1 mL) was added DIEA (95 μL, 0.54 mmol) followed by isobutyryl chloride (17 μL, 0.16 mmol). After stirring at room temperature for 16 hours the mixture was treated with 1N HCl (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with brine (10 mL) then dried over Na2SO4 and concentrated. The residue was chromatographed (4:1 to 2:1 hexanes/EtOAc) to afford the product (31 mg, 62%) as a colorless gum. MS ESI (+) m/z 458.1 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 3H), 7.36 (m, 3H), 7.17 (m, 2H), 3.33 (m, 3H), 3.04 (m, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 1.77 (m, 1H), 1.56 (m, 1H), 1.16 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([N:6]([C:10](=[O:22])[C@H:11]([OH:21])[C@@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]Cl)=[CH:4][CH:3]=1.CN(C=O)C>CC(O)(C)C.CS(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([N:6]2[CH2:7][CH2:8][O:21][C@H:11]([C@@H:12]([OH:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]2=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)N(CCCl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(Cl)cc2)C1=O
Yield: 24.9 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 60-4 (1.78 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 60-5 (400 mg) as a pale yellow amorphous solid.
Reaction SMILES: O(C)[Na].Cl.[NH2:5][OH:6].[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:10]([Cl:20])[CH:9]=1>CO>[NH2:7][C:8]1[CH:9]=[C:10]([Cl:20])[C:11]([C:15]([CH3:18])([CH3:19])[C:16](=[N:5][OH:6])[NH2:17])=[C:12]([Cl:14])[CH:13]=1
Reactant: NO
Reactant: CC(C)(C#N)c1c(Cl)cc(N)cc1Cl
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CC(C)(C(N)=NO)c1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Yield: 26 %

Procedure:
NaOCH3 30% (0.592 mole) was added to a solution of hydroxylamine hydrochloride (0.1085 mole) in CH3OH (200 ml), stirred at RT. The mixture was stirred for 10 minutes. Intermediate (3) (0.0542 mole) was added portionwise and the resulting reaction mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was partitioned between CH2Cl2 and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off, washed with DIPE, and dried, yielding 3.7 g (26%) of 4-amino-2,6-dichloro-N′-hydroxy-α,α-dimethylbenzeneethanimidamide (intermediate 17).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: NCCN
Reactant: CC(C#N)c1cc(Cl)ccc1Cl
Product: CC(C1=NCCN1)c1cc(Cl)ccc1Cl

Procedure:
rac-2-[1-(2,5-Dichloro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,5-dichloro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (ISP): 243.0 ((M+H)+.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][OH:12])[CH:4]=[CH:3]1.C([Li])CCC.[C:18](=[O:20])=[O:19].O>C(OCC)C.CCCCCC>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4]2
Reactant: Cn1ccc2cccc(CO)c21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: Cn1c(C(=O)O)cc2cccc(CO)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon a solution of 4 g (1-methyl-1H-indol-7-yl)-methanol in 80 ml diethyl ether is added dropwise to 76 ml of a 1.6 M solution of n-butyllithium in hexane at 0° C., while the temperature does not exceed 35° C. Then the mixture is stirred for another 12 hours at ambient temperature and the solution thus obtained is poured onto 30 g of crushed dry ice in 100 ml diethyl ether. The mixture is stirred until all the dry ice has dissolved and the reaction is then stopped by the addition of 40 ml of water. The phases are separated and the organic phase is extracted twice with 20 ml of water. The combined aqueous phases are suction filtered and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. The solid precipitated is suction filtered and dried in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH2:36][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.54 mmol) and acetic acid (0.03 ml, 0.54 mmol) were added to solution of 2-([(3,4-difluorophenyl)methyl]oxy)-5-formyl-N-3-pyridinylbenzamide (may be prepared by Example 80; 200 mg, 0.54 mmol) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (173 mg, 0.81 mmol) was then added and the mixture was warmed to 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml), the organic were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 82 mg.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[NH3:15]>CO>[F:12][C:5]([F:13])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([NH2:15])=[O:3]
Reactant: N
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Solvent: CO
Product: NC(=O)C(F)(F)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of the above difluoro-phenyl-acetic acid ethyl ester and NH3 in MeOH (7 M, 10 mL) is heated to 60° C. for 2 h in a pressure tube. The mixture is cooled to room temperature, and concentrated to afford 2,2-difluoro-2-phenyl-acetamide (0.33 g). LCMS: RT=1.7 minutes; MS: 172 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[N:12]1([NH2:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N:12]1([NH:18][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(NN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 48 h
Yield: 257 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (6.7 g, 40 mmol), morpholin-4-ylamine (10.0 g, 9.8 mmol) and anhydrous potassium carbonate (6.1 g, 44 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 120° C. under nitrogen for 2 days. Sample NMR analysis showed almost complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (100 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford N1-Morpholin-4-yl-4-nitro-benzene-1,3-diamine (6.0 g, 63%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[C:26](I)=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[F:18][C:19]1[C:26]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[CH3:17])=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: COc1ccc(C=O)c(F)c1I
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3c(OC)ccc(C=O)c3F)cc21
Yield: 59 %

Procedure:
The intermediate 2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde (example 7b). 59% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.31 (s, 3 H), 1.34 (s, 3 H), 1.60 (s, 2 H), 2.10 (s, 3 H), 2.52 (s, 2 H), 3.88 (s, 3 H), 4.02 (q, J=7.2 Hz, 1 H), 6.82 (s, 1 H), 6.93 (d, J=9.0 Hz, 1 H), 7.22 (s, 1 H), 7.95 (t, J=8.1 Hz, 1 H), 10.26 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:22]=[CH:21][C:13]([O:14]C(C)(C)C(O)=O)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OC1C=CC(C(O)=O)=CC=1.ClC1C=CC(CN)=CC=1.C1(C)C=C(C)C=C(C)C=1.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8](=[O:9])[C:10]2[CH:22]=[CH:21][C:13]([OH:14])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(C(=O)NCc2ccc(Cl)cc2)cc1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NCc1ccc(Cl)cc1
Agent: O=C(O)c1ccc(O)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: O=C(NCc1ccc(Cl)cc1)c1ccc(O)cc1

Procedure:
FIG. 2 illustrates a general reaction scheme for the preparation of 2(4-(((4-chlorobenzyl)amino) carbonyl)phenoxy)-2-methyl propionic acid. In accordance with the illustrated scheme, 3.5 g (25 mmol) of p-hydroxybenzoic acid (PBA), 6.07 g (50 mmol) of 4-chlorobenzyl amine and mesitylene are added together for a total volume of 25 milliliters (ml) and this volume is heated to reflux. To this refluxing mixture is added 0.88 g (6.5 mmol) phosphorous pentachloride (PCl5) and refluxing is continued for an additional hour. The cooled reaction mixture is washed with 10 ml of 1 normal (1N) hydrochloric acid (HCl) and extracted with 10 ml of 2N sodium hydroxide (NaOH). The combined alkali layer is washed with ether, then cooled and acidified with 1N HCl to provide 4.2 g of N-(4-chorobenzyl)-4-hydroxybenzamide which has the formula C14H12ClNO2 as an intermediate product (81% yield), mp. 190°-192° C. The intermediate product is recrystallized from a 1:2 acetone:petroleum ether solution and a 1.3 g (5 mmol) portion is O-alkylated. Then 2.75 g of pulverized sodium hydroxide is added to a cooled and stirred solution of the reaction intermediate, N-(4-chlorobenzyl)-4-hydroxybenzamide, where 1.3 g (5 mmol) of N-(4-chlorobenzyl)-4-hydroxybenzamide is present in acetone for a total volume of 25 ml. Subsequently, 1.25 ml (10.4 mmol) of chloroform is added dropwise to the solution over 10 minutes. The reaction mixture is stirred overnight at room temperature and acetone is removed under vacuum. The residue is dissolved in 10 ml of water, washed with ether, and then cooled and acidified with dilute hydrochloric acid to produce a yellow precipitate of 2(4-(((4-chlorobenzyl)amino)carbonyl)phenoxy)2-methyl propionic acid which is indicated in FIG. 2. The precipitate is purified via extraction with aqueous sodium bicarbonate followed by acidification, using dilute HCl, of the alkaline layer. The resulting propionic acid is then crystallized from a 1:2 acetone:petroleum ether mixture to produce a compound having the formula C18H18ClNO4 in a 50% yield or 0.86 mg. The crystallized product has a melting point of 180° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[N:16]2[C:12]([S:13][CH:14]=[CH:15]2)=[N:11][C:10]=1[CH3:17])=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:10]1[N:11]=[C:12]2[N:16]([C:9]=1[C:7]1[O:8][CH2:2][C:3](=[O:4])[NH:5][N:6]=1)[CH:15]=[CH:14][S:13]2
Reactant: Cc1nc2sccn2c1C(=O)NNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c1C1=NNC(=O)CO1
Yield: 37.5 %

Procedure:
A mixture of 16 g of N'-chloroacetyl-6-methylimidazo[2,1-b]thiazole-5-carbohydrazide and 14 g of potassium carbonate in 160 ml of dimethylformamide is stirred under heating at 50°-60° C. for 4 hours. After insoluble substances are filtered off, the dimethylformamide is distilled off and to residual oil is added ethanol. The precipitated crystals are collected by filtration and recrystallized from methanol to give 5.2 g of 2-(6-methylimidazo[2,1-b]thiazol-5-yl)-4,6-dihydro-1,3,4-oxadiazin-5-one as pale yellow crystals, melting at 274°-275° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)nc1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (3.83 g, 18.1 mmol) in 1,2-dimethoxyethane (30 ml) was added sodium hydride (60% in oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (9.30 g, purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene-toluene:ethyl acetate=5:1) to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (6.67 g, 88%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][CH3:20])=[S:18])[C:6]=2[CH:21]=1.NCCCOC1C2C=CC=CC=2OC(=O)C=1>>[CH3:20][NH:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[C:6]2[CH:21]=[CH:2][CH:3]=[CH:4][C:5]=2[O:10][C:9](=[O:11])[CH:8]=1)=[S:18]
Reactant: CNC(=S)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Agent: NCCCOc1cc(=O)oc2ccccc12
Product: CNC(=S)NCCCOc1cc(=O)oc2ccccc12

Procedure:
Is prepared according to the procedure for 1-[3-(6-chloro-2-oxo-2H-1-benzopyran-4-yloxy)-propyl]-3-methyl-thiourea from 4-(3-amino-propoxy)-1-benzopyran-2-one (trifluoroacetic acid salt) to afford the title compound after HPLC purification (71 mg, 73%). 1H NMR (DMSO-d6, 300 MHz) δ 7.87 (1H, dd, J=1.5, 7.75 Hz), 7.67 (1H, m), 7.56 (1H, br s), 7.39 (3H, m), 5.88 (1H, s), 4.24 (2H, t, J=6 Hz), 3.59 (2H, s), 2.79 (3H, s), 2.07 (2H, m); MS (ESI, Pos.) calcd for C14H16N2O3S m/z [M+H]=292.1, found 292.4.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:17][C:15]1([CH3:18])[CH2:14][O:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:7][CH:8]=2)=[N:16]1
Reactant: C1CCNCC1
Reactant: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Product: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (0.5 g, 1.87 mmol, 1 eq) and piperidine (0.37 ml, 3.73 mmol, 2 eq) is stirred in a sealed tube at 100° C. overnight. The mixture is then concentrated under vacuum to give 0.8 g of an orange solid. This solid is purified by chromatography on silica gel (eluent: dichloromethane/ethanol 95:5) to obtain 0.49 g of 1-{3-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 1 as an orange oil.
Reaction SMILES: [ClH:1].[O:2]=[S:3]1(=[O:16])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]1[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.O=S1(=O)N(C)CC[N:19]1C1C=CC([N+]([O-])=O)=CC=1>>[ClH:1].[O:16]=[S:3]1(=[O:2])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]1[C:9]1[CH:15]=[CH:14][C:12]([NH:13][NH2:19])=[CH:11][CH:10]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)S1(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)S1(=O)=O
Agent: Cl
Product: CN1CCN(c2ccc(NN)cc2)S1(=O)=O
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield from 4-(1,1-dioxo-5-methyl-1,2,5-thiadiazolidin-2-yl)aniline hydrochloride using a similar method to that described for Intermediate 1 (step 1); yellow solid; δH (360 MHz, DMSO-d6) 7.15 (2H, d, J=8.9 Hz, Ar--H), 6.92 (2H, d, J=8.9 Hz, Ar--H), 3.74 (2H, t, J=6.4 Hz, --CH2 --), 3.42 (2H, t, J=6.4 Hz, --CH2 --), 2.68 (3H, s, --CH3); m/z (FAB) 243 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]1[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]1=[O:21].S>[NH4+].[OH-].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]1[C:17](=[O:18])[CH2:16][C:15]([CH3:19])([CH3:20])[CH2:14][C:13]1=[O:21]
Reactant: CC1(C)CC(=O)C(c2c(Cl)cc([N+](=O)[O-])cc2Cl)C(=O)C1
Agent: S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)C(c2c(Cl)cc(N)cc2Cl)C(=O)C1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A solution of 20.0 g (0.0606 mol) of 2-(2',6'-dichloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione in 150 ml conc. NH4OH and 150 ml of ethanol was stirred at room temperature while passing H2S gas through the solution at such a rate that all of the H2S was absorbed. After the solution was saturated with H2S, it was refluxed 24 hours while continuously passing H2S slowly through the solution. The reaction mixture was cooled to room temperature, the precipitated sulfur removed by filtration, and the filtrate evaporated to dryness under reduced pressure. To the residue was added 300 ml of 0.25 N NaOH, and the solution filtered once more. The filtrate was cooled and acidified to pH-4 with 6 N HCl. A tan solid formed which was collected by filtration to give 11.2 g when dry. This material was washed with methylene chloride to give 8.2 g (45%) of 2-(2',6'-dichloro-4'-aminophenyl)-5,5-dimethyl-1, 3-cyclohexanedione as a white powder, m.p. 243° d.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH:15][C@@H](C3C=CC=CC=3)C)[CH2:6][C:5]2=1.CO.CC(O)=O>C1COCC1.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH2:15])[CH2:6][C:5]2=1
Reactant: C[C@@H](N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a degassed solution of (S)-6-fluoro-N—((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (8.96 g, 0.029 mol) in a mixture of THF (60 ml), MeOH (20 ml) and AcOH (10 ml) was added 20% Pd(OH)2 (1.34 g). The mixture was evacuated three times and the reaction was set under 1 atm (balloon) H2. It was stirred at rt for 10 h and filtered over celite. The pad was rinsed with THF/MeOH and the filtrate was concentrated to 50 ml. The residue was dissolved in EA, and washed with 1N NaOH. The aqueous phase was extracted with EA and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].Cl.C[O-].[Na+].[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CO.CN(C=O)C>[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(N)=O

Procedure:
0.56 mg (5 mmol) of H-Gly-NH2.HCl are dissolved in 20 ml MeOH and 270 mg (5 mmol) NaOMe added. Stirring takes place for 10 min and the solvent is removed under vacuum. To the residue are added 15 ml DMF, 1.07 g (5 mmol) Boc-Pro-OH, 1.2 g (6.0 mmol) EDCI, 0.9 g (6 mmol) HOBT and 0.825 ml (7.5 mmol) NMM and stirring takes place for 16 hours. To the reaction mixture are added 10 g of mixed-bed ion exchanger (Merck ion exchanger V), stirring takes place for 0.5 hours, followed by filtering and washing with 10 ml MeOH. The filtrate is concentrated under vacuum, the resulting oil absorbed in 150 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5N HCl, 10% NaHCO3 solution and H2O respectively.