Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][CH2:21][C@H:22]1[CH2:24][C@H:23]1[CH2:25][OH:26])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][CH2:21][C@H:22]1[CH2:24][C@H:23]1[CH2:25][O:26][N:28]1[C:32](=[O:33])[C:31]2[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]1=[O:38])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H]1CON1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2.61 ml (0.0157 mol) of diethyl azodicarboxylate (93%) in 15 ml of benzene is added dropwise to a mixture of 3 g (0.0149 mol) of cis-2-(N-BOC-aminomethyl)-cyclopropanemethanol, 2.43 g (0.0149 mol) of N-hydroxyphthalimide, 3.9 g (0.0149 mol) of triphenylphosphine and 120 ml of benzene at 20°-30° C., while stirring. The reaction mixture is stirred at room temperature for 16 hours and filtered, the crystalline residue is washed with benzene and the filtrate is evaporated in vacuo. The residue is purified by means of flash chromatography on silica gel using hexane and hexane/ethyl acetate (2:1). After evaporation of the product-containing fractions and crystallization of the residue from methanol/hexane, the title compound is obtained, m.p. 96°-97° C.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=1[O:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=3[O:29][CH3:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122.8 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol), K2CO3 (3.0 g 21.8 mmol), acetonitrile (125 ml) and a catalytic amount of KI was heated to reflux and stirred under nitrogen for 24 hours. At this point, an additional amount of K2CO3 (1.0 g, 7.2 mmol) and alkylating agent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating at reflux was resumed for 24 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed with acetonitrile and the filtrate was concentrated to afford a dark oil. The oil was extracted with methylene chloride, and the organic extract was washed with water, dried with MgSO4 and concentrated to yield 9.2 g of an oil. Purification by preparative HPLC (Waters Associates Prep LC/System 500 utilizing 2 silica gel columns and 3% methanol/methylene chloride as eluent) provided 3.8 g of a soft, beige gum, which readily solidified. The compound was recrystallized twice from ethanol to give 2.1 g (28%) of 1-]4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxyl]-3-methoxyphenyl]ethanone as a beige solid, m.p.=98°-100° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH:34]([C:44](O)=[O:45])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[N:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([NH2:62])[CH:60]=3)[N:55]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=2)=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]1([CH:36]2[CH2:35][CH:34]([C:44](=[O:45])[NH:62][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[N:55]([C:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=[C:53]4[C:50]3[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=3)[CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccccc2)C1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 0.129 mmol) was added to a suspension of 1-(tert-butoxycarbonyl)-5-phenylpiperidine-3-carboxylic acid (36 mg, 0.117 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.117 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccccc1Nc1nc(Cl)nc2ccccc12
Product: COc1ccccc1N(C)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide by a procedure similar to example 7 (72% yield). 1H NMR (CDCl3): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:26]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(C)c1ccc(N)cn1
Product: CN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to the example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-dimethylamino-pyridin-3-yl)-amide was prepared from 2-phenyl-trifluoromethyl-oxazole-4-carboxylic acid and N2,N2-dimethyl-pyridine-2,5-diamine. LCMS calcd for C18H15F3N4O2 (m/e) 376.34 obsd 377.12 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11](I)([F:13])[F:12]>CN(C)C=O.O.[Cu]>[F:10][C:11]([F:13])([F:12])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(F)(F)F)c1

Procedure:
A solution of 5-iodo-m-xylene (2.3 g) in dimethylformamide (DMF)(30 ml) and copper bronze (0.65 g) in a stainless steel tube is cooled and treated with trifluoromethyliodide (15 g). The tube is sealed and heated at 130°-140° C. in a rocking autoclave for 6 hours. After cooling and venting, the reaction mixture is diluted with water and extracted with n-hexane (2×200 ml). The combined hexane extracts are washed with aqueous NaHCO3 and water. After drying over MgSO4, the solvent is removed under reduced pressure. The residue is subjected to chromatography over silica gel to yield purified 5-(trifluoromethyl)-m-xylene.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(C2CCCC2)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CCCC3)n[nH]2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2,4-Dichloroquinazoline (0.657 g, 3.3 mmol) in ethanol (9 ml) was treated with 3-amino-5-cyclopentyl pyrazole (0.5 g, 3.3 mmol) and triethylamine (0.46 ml, 3.3 mmol) and stirred overnight at room temperature. The mixture was filtered and the solid washed with ethanol to give (2-chloro-quinazolin-4-yl)-(5-cyclopentyl-2H-pyrazol-3-yl)-amine as colourless crystals (684 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]1([CH2:19][CH2:20][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(C)(C)C1CCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 88.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3-tert-butylcyclopentanone (750 g, 5.36 mol) and pyrrolidine (362 mg, 5.092 mol) in methanol was refluxed overnight. The reaction mixture was removed in vacuo. The residue was diluted with an equal volume of H2O and then added HCl until pH=1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (0.8 g, 89%). 1H NMR (CDCl3): 0.77 (s, 9H), 1.34 (m, 1H), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, 1H), 7.47 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: OC1C=C(C=C(C#N)C=1O)C(O)=O.[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[C:28]([C:34]#[N:35])[C:29]=1[O:30][CH2:31][CH:32]=[CH2:33])[C:21]([O:23]CC=C)=[O:22])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[C:28]([C:34]#[N:35])[C:29]=1[O:30][CH2:31][CH:32]=[CH2:33])[C:21]([OH:23])=[O:22])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)c1cc(C#N)c(OCC=C)c(OCC=C)c1
Agent: N#Cc1cc(C(=O)O)cc(O)c1O
Product: C=CCOc1cc(C(=O)O)cc(C#N)c1OCC=C

Procedure:
3,4-Dihydroxy-5-cyanobenzoic acid, (see GB 2 200 109) was converted, essentially as above, to allyl 3,4-diallyloxy-5-cyanobenzoate: NMR (CDCl3) 4.63 (m, 2H); 4.77-4.87 (m, 4H); 5.23-5.51 (m, 6H); 5.92-6.18 (m, 3H); 7.76 (d, 1H); 7.86 (d, 1H). This ester was hydrolysed as above to give 3,4-diallyloxy-5-cyanobenzoic acid: NMR (DMSO-d6) 4.72-4.84 (m, 4H); 5.23-5.51 (m, 4H); 5.93-6.18 (m, 2H); 7.79 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH2:17][C:16]2[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:15]=2[F:14])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: COc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 4-chloro-2-methoxy-5-nitrophenol (0.67 g) and 2-fluoro-6-methoxy-benzyl bromide (0.66 g) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.54 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (diethyl ether/n-hexane=1/3), and dried under reduced pressure to give 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitroanisole (0.97 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution were added methanol (15 mL) and nickel(II) bromide (31 mg). To the mixture was added sodium borohydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16](=[O:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[NH2:15][C:16](=[O:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: NC(=O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NC(=O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
2.5 g of 2-bromoacetamide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(2-amino-2-oxoethylthio)benzoate. 2.6 g of methyl 4-(2-amino-2-oxoethylthio)benzoate was reacted via Procedure R to give methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate. 1 g of methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(2-amino-2-oxoethylsulfonyl)benzoic acid. 150 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 430.2 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N:10]=2)=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[Cl:15][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cccc(-c2ccc(CBr)cc2)n1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2cccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.8 %

Procedure:
The mixture (5.72 g) obtained in Example 36-2 and potassium phthalimide (2.04 g) were dissolved in DMF (30 ml) and the whole was stirred at room temperature for 24 hours. Then, a solid component was separated by filtration. After the solvent was distilled off, the resultant was dissolved in chloroform and washed with a aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform and dried with anhydrous magnesium sulfate. The solvent was distilled off. The resultant residue was purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (1.56 g) as a colorless solid.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>CCCCCC.CCOCC>[OH:15][C:11]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: c1cscn1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCC1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of n-BuLi (36 mL of a 2.5M solution in hexane, 90 mmol) in anhydrous ether (100 mL) at −78° C. was slowly added a solution of thiazole (6.35 g, 74.6 mmol) in anhydrous ether (60 mL). The resulting mixture was stirred for 1 h and then cyclobutanone (10.4 g, 148 mmol) in ether (20 mL) was added over 5 min. The mixture was stirred for 2 h at −78° C. and then sat. aq. NH4Cl was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided 2-[(1-Hydroxy)cyclobutyl]thiazole (5 g).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22](=[O:24])[CH3:23])=[C:16]([N+:25]([O-])=O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:25][C:16]1[CH:15]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:22](=[O:24])[CH3:23]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1

Procedure:
A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31. g), 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. 1H NMR (CDCl3): 7.408-7.298 (5H, m), 7.130 (1H, s), 6.155 (2H, br), 6.104 (1H, s), 5.134 (2H, s), 3.834 (3H, s),2.507 (3H, s). LC/MS (M+1=272).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[CH:30][O:29][N:28]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:32]>ClCCl.C(OCC)(=O)C>[ClH:32].[ClH:32].[O:29]1[CH:30]=[N:31][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:22][CH:23]=2)=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(-c3ncon3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1nc(-c2ccc(C3CNCCN3)cc2)no1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 1,4-di(t-butoxycarbonyl)-2-(4-(1,2,4-oxadiazol-3-yl) phenyl)piperazine (464 mg, 1.08 mmol) in dichloromethane (2 mL) was added 4 N hydrogen chloride in ethyl acetate (3 mL) at room temperature. After stirring for 1.5 h, the precipitate was collected and dried in vacuo to afford 2-(4-(1,2,4-oxadiazol-3-yl)phenyl)piperazine dihydrochloride (321 mg, 98%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:27])/[CH:5]=[C:6](\[CH3:26])/[CH:7]=[CH:8]/[CH:9]1[CH2:11][CH:10]1[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:26]/[C:6](/[CH:7]=[CH:8]/[CH:9]1[CH2:11][CH:10]1[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)=[CH:5]\[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(/C=C/C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C)=C\C(=O)O

Procedure:
8.84 g of (2E,4E)-3-methyl-5-[(1RS,2RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid ethyl ester (ca. 94% pure according to 1H-NMR) was dissolved in 100 ml of THF/EtOH=1:1 and treated with 40 ml of 3N aq. NaOH. The reaction mixture was kept in the dark at ambient temperature for three days. It was then poured onto crashed ice, extracted with EtOEt, washed with H2O, and dried over Na2SO4. Evaporation of the solvent and twofold crystallisation (hexane/AcOEt=8:2 and 7:3) yielded 4.25 g of (2E,4E)-3-methyl-5-[(1RS,2RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid as white crystals of m.p. 150°-151° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:58][C:59]([NH2:66])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH2:61]>CN(C=O)C>[NH2:66][C:59]([CH3:58])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH:61][C:24]([C:23]1[N:5]2[CH:6]=[C:7]([CH3:22])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:16])([F:15])[F:17])[C:18]([F:19])([F:20])[F:21])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: CC(C)CC(C)(N)CN
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NCC(C)(N)CC(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 mg (0.08 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 259A, dissolved in 0.3 ml of DMF, 40 mg (0.104 mmol) of HATU, dissolved in 0.3 ml of DMF, and then 16 mg (0.16 mmol) of 4-methylmorpholine were added to 10 mg (0.08 mmol) of rac-2,4-dimethylpentane-1,2-diamine. The mixture was shaken at RT overnight. The target compound was concentrated by preparative HPLC (Method 12). This gave 10 mg (25% of theory).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15].[Li]C(CC)C.[Br:30]C(F)(F)C(F)(F)Br>C1CCCCC1.C1COCC1>[Br:30][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:19]=1[SH:24]
Reactant: CC(C)(C)c1ccccc1S
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)c1cccc(Br)c1S
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2M solution in cyclohexane) at 23° C. The resulting solution is cooled to 0° C. A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10° C. The reaction is then stirred at 0° C. for 5 h and is then allowed to warm to 23° C. overnight. To the resulting yellow solution at 23° C. is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3M solution in cyclohexane) over 0.5 h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2-dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1N HCl (80 mL), and extracted with hexanes (3×100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 g). This oil is taken up in 1N NaOH (100 mL), and extracted with CH2 Cl2 (3×50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12N HCl, and extracted with CH2Cl2 (3×100 mL). The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil.