Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]([F:8])([F:7])[F:6])=O.[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1.O>COCCOC>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]2=[N:17][C:3]([C:5]([F:8])([F:7])[F:6])=[CH:2][N:14]2[N:13]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COCc1nnc(N)s1
Solvent: COCCOC
Solvent: O
Product: COCc1nn2cc(C(F)(F)F)nc2s1
Temperature: 80 °C
Yield: 47 %

Procedure:
Bromotrifluoroacetone (478 g, 1.05 eq) is added on a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a25 (346 g, 1 eq) in 1,2-dimethoxyethane (6 l) at 20° C. The reaction mixture is heated to 80° C. until maximum conversion (<24 h). Water (4 l) is added to the reaction mixture at 32° C. and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10° C. to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1.5 l) to afford 266 g of pure 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a28.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]>S(Cl)(Cl)=O>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:16])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
Thionyl chloride (10 ml) was added to 5.0 g (19.5 mmol) of 4-(4-n-propyloxyphenyl)benzoic acid synthesized in the step (ii), and the mixture was refluxed overnight. After an excess amount of thionyl chloride was removed from the resultant mixture, 4′-(n-propyloxy)-4-(tert-butoxycarbonyl)biphenyl was obtained in the same manner as in the Example 104.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:26]([C:29]1[CH:42]=[CH:41][C:32]([O:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([O:40][C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:41]=[CH:42][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)=[CH:39][CH:38]=3)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 93.2 %

Procedure:
2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)phenoxypropionic acid chloride hydrochloride (0.7 g) and 4-(4-nitrophenoxy)phenol (0.5 g) were dissolved in dry tetrahydrofuran (10 ml), and stirred with an addition of triethylamine (0.5 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure and the residue was dissolved in methylene chloride (20 ml), followed by washing with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride After drying over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue obtained was purified by medium pressure column chromatography by using silica gel, to obtain 4-(4-nitrophenoxy)phenyl 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate (0.9 g) (oily product).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[CH2:34]([O:41][C:42]1[N:43]=[N:44][C:45]([C:56]#[CH:57])=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:34]([O:41][C:42]1[N:43]=[N:44][C:45]([C:56]#[C:57][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)(F)c1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Temperature: 80 °C
Yield: 10 %

Procedure:
A microwave vial was charged with 5-iodo-2-(trifluoromethyl)pyridine (617 mg, 2.260 mmol), copper(I) iodide (39.1 mg, 0.205 mmol), bis(triphenylphosphine)palladium(II) chloride (72.1 mg, 0.103 mmol), 1,8-diazabicycloundec-7-ene (DBU; 1858 μl, 12.33 mmol) and tetrahydrofuran (6849 μl). The reaction mixture was then purged and evacuated with nitrogen and to this was then added 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5: 650 mg, 2.1 mmol). The reaction was heated to 80° C. whilst being subjected to microwave radiation for 1 hour. Upon cooling the reaction mixture was partitioned between ethyl acetate and water, at which point a solid formed which was filtered and discarded. The organics were then washed with water and brine, dried (MgSO4), filtered and concentrated to afford a brown oil. This was purified by silica chromatography (eluting with 0-100% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine as a yellow amorphous solid (yield=10%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:13][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: BrCCCCBr
Reactant: COc1ccc(O)c(OC)c1OC
Product: COc1ccc(OCCCCBr)c(OC)c1OC

Procedure:
The procedure is as for Example 53, Step A, using as substrate 2,3,4-trimethoxyphenol and 1,4-dibromobutane.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)NCCCCc1cccnc1
Yield: 90 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (25.85 g) and 3-pyridinebutanamine (10 g) in tetrahydrofurane (100 mL) was stirred for 18 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to afford 23.9 g of (E)-5,5-bis(3-fluorophenyl)- N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 103°-104° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([C:15]#[N:16])[C:9]=1[N+:17]([O-:19])=[O:18].[CH2:20](I)[CH3:21]>CN(C=O)C>[Cl:14][C:12]1[N:11]=[C:10]([C:15]#[N:16])[C:9]([N+:17]([O-:19])=[O:18])=[C:8]([NH:7][CH2:20][CH3:21])[CH:13]=1
Reactant: CCI
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
At room temperature, potassium carbonate (3.06 g) was added by portions to a solution of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (4.0 g) in DMF (60 mL). A solution of ethyl iodide (3.46 g) in DMF (20 mL) was added dropwise to the mixture, then stirred for 24 h at room temperature and concentrated under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (3×50 ml), then concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: dichloromethane) to afford the title compound (2.94 g) as yellow crystals (mp=120° C.). 1H NMR (DMSO-d6) δ: 8.67 (br. s, 1H); 7.46 (s, 1H); 3.51 (q, J=8 Hz, 2H); 1.21 (t, J=8 Hz, 3H). MS m/z: 227/229 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)=O>[Ir].CO>[CH2:1]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Ir]
Solvent: O=CO
Solvent: CO
Product: c1ccc(CNCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
Under an argon-gas atmosphere, 5 mL of dehydrated methanol, 505 μL (5.0 mmol) of benzaldehyde (MW: 106.12), 545 μL (5.0 mmol) of benzylamine (MW: 107.15), 566 μL (15.0 mmol) of formic acid (MW: 46.43), and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and the mixture was stirred while heating at 60° C. for 1.5 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product dibenzylamine. Its conversion rate was 100% based on NMR measurement, with 95% of dibenzylamine, 3% of tribenzylamine, and 2% of benzyl alcohol.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:12])([CH3:11])[CH3:10])(C)(C)C.O1CCOCC1.Cl>C(Cl)Cl>[NH2:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([CH3:11])([OH:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)C(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(O)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl(2-hydroxy-2-methyl-1-phenylpropyl)carbamate (3.5 g, 13 mmol) in CH2Cl2 (20 mL) was added dioxane saturated with HCl gas (10 mL) and the contents were stirred at ambient temperature for 30 min. The volatiles were then removed under reduced pressure and the residue thus obtained was triturated with Et2O to afford (S)-1-amino-2-methyl-1-phenylpropan-2-ol. 1H NMR (300 MHz, DMSO-d6) δ 8.3 (bs, 2H), 7.47-7.37 (m, 5H), 5.34 (s, 1H), 4.1 (bs, 1H), 1.17 (s, 3H), 0.97 (s, 3H). Anal. Calcd. C10H15NO 165.2. Found 166.2 (M+H).
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].N([O-])=O.[Na+].OS(O)(=O)=O>O>[C:8]([CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1)([OH:10])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(C(=O)O)O1
Reaction time: 12 h

Procedure:
In 200 ml. of water is suspended 29.4 g. (0.2 M) of H.Glu.OH, and a solution of 16.8 g. (0.24 M) of sodium nitrite in 120 ml. of water and 120 ml. of 2N-H2SO4 are simultaneously added dropwise at room temperature over a period of about 90 minutes. The reaction mixture is allowed to stand for 12 hours. The water is distilled off under reduced pressure and hot acetone is added to the residue. The acetone is distilled off from the extract and the oily residue is purified by distillation under reduced pressure. The desired compound is obtained as a distillate between 170.0 and 175.0° C/O 5 mmHg. Yield 14.3 g. (55.0%); melting point: 50° C; optical rotation [α]D27 -11.4° (c=0.77, in 2N-NaOH).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CC(CN1CCCCC1)Oc1ccc(I)cc1
Product: CC(CN1CCCCC1)Oc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-propyl]-piperidine (173 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([O-:19])=O)=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20]>>[CH:1]([S:14]([CH2:16][C:17]([NH2:20])=[O:19])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])CS(=O)C(c1ccccc1)c1ccccc1
Reactant: N
Product: NC(=O)CS(=O)C(c1ccccc1)c1ccccc1

Procedure:
Lafon also disclosed the use of an intermediate, a racemic mixture of benzhydrylsulphinylacetic acid to prepare an isomer of modafinil in U.S. Pat. No. 4,927,855, referring to French patent 2,326,181B. The racemic mixture of the acid was reacted with the (−)-α-methylbenzylamine to provide the (−)-benzhydrylsulphinylacetate of (−)-methylbenzylamine which is acidified with concentrated hydrochloric acid to provide (−)benzyhydrylsulphinylacetic acid. The levo-acid thus produced was then reacted with methylsulfate in water and sodium bicarbonate to provide methyl(−)benzhydrylsulphinylacetate. The acetate was then amidated with ammonia gas to provide (−)benzhydrylsulphinylacetamide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([CH3:31])[CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[C:24]([CH3:31])[CH:23]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(Cl)ccc1C(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:17][CH2:16][Br:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCCBr
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: BrCCCOC(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a reactor fitted with a water trap, a mixture of benzhydrol (5.0 g), 3-bromo-1-propanol (3.8 g), camphor-10-sulfonic acid (1.0 g), and toluene (80 mL) was refluxed for 2 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to provide 7.0 g of the title compound. Yield 85%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH:24]=[O:25])[CH:7]=1.[BH4-].[Na+]>CO.C(O)(=O)C.O>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH2:24][OH:25])[CH:7]=1
Reactant: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2CO)on1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 1.2 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-formylphenoxy]pentyl}-3-methylisoxazole (Example 70) in 10 ml of methanol was added in portions 0.2 g of sodium borohydride. The mixture was stirred for one hour, then treated with a few drops of glacial acetic acid and diluted to 50 ml with water. The solid product was collected, washed with aqueous methanol and recrystallized from ethyl acetate to give 1.2 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-hydroxymethylphenoxy]pentyl}-3-methylisoxazole, m.p. 140°-141° C.
Reaction SMILES: C([N:8]1[C:12]([CH2:13][C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=2[CH2:19][CH3:20])=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.[Na].N>>[CH2:21]([N:17]1[C:18]([CH2:19][CH3:20])=[C:14]([CH2:13][C:12]2[NH:8][CH:9]=[N:10][CH:11]=2)[C:15]([CH2:23][CH3:24])=[N:16]1)[CH3:22]
Reactant: CCc1nn(CC)c(CC)c1Cc1cncn1Cc1ccccc1
Agent: N
Agent: [Na]
Product: CCc1nn(CC)c(CC)c1Cc1cnc[nH]1

Procedure:
1,3,5-Triethyl-4-(3H-imidazol-4-ylmethyl)-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-1,3,5-triethyl-1H-pyrazole by debenzylation with sodium in liquid ammonia for 10 min. The blue reaction mixture was quenched by addition of solid ammonium chloride, the ammonia evaporated and the residue distributed between water and t-butyl methyl ether. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. 1,3,5-Triethyl-4-(3H-imidazol-4-ylmethyl)-1H-pyrazole was obtained as light yellow solid; MS (ISP): 233.0 ((M+H)+.).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:24]([OH:26])=O)=[N:11][C:12]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[C:13]([F:15])[CH:14]=1)=O)(C)(C)C.[NH2:27][C:28]1[C:29]([N:37]2[CH2:42][C@H:41]([CH3:43])[CH2:40][C@H:39]([NH:44]C(=O)OC(C)(C)C)[CH2:38]2)=[C:30]2[CH2:36][CH2:35][O:34][C:31]2=[N:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[C:10]([C:24]([NH:27][C:28]2[C:29]([N:37]3[CH2:42][C@H:41]([CH3:43])[CH2:40][C@H:39]([NH2:44])[CH2:38]3)=[C:30]3[CH2:36][CH2:35][O:34][C:31]3=[N:32][CH:33]=2)=[O:26])=[N:11][C:12]([C:16]2[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=2[F:22])=[C:13]([F:15])[CH:14]=1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)c(F)cc3N)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a mixture of 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (16.1 mg, 0.0437 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (14.0 mg, 0.0402 mmol) and HATU (53.1 mg, 0.140 mmol), DMF (1.0 mL) was added followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.9 mg, 29%). LCMS calc. for C25H26F3N6O2 (M+H)+: m/z=499.2. found 499.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(OCC)(=O)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
To a solution of 2,5-dichloropyridine (2 g) in dimethylformamide (30 mL) was added potassium carbonate (3.73 g) and piperazine (1.16 g) and the mixture was stirred at 110° C. for 4 hours. After cooling the reaction mixture, thereto was added ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, solvent: chloroform/methanol=100/0 to 99/1) to obtain 5-chloro-2-(1-piperazinyl)pyridine (0.28 g, Yield: 10%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:52][O:53][C:54](=[O:59])[C@H:55]([CH2:57][OH:58])[NH2:56].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:56][C@@H:55]([CH2:57][OH:58])[C:54]([O:53][CH3:52])=[O:59])=[O:23])[O:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)Nc1ccccc1F
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid (example 105, step 2, 1 g, 293 mmol) was dissolved in DMF (20 ml) and, to it N,N′-Dicyclohexyl carbodiimide (724 mg, 3.51 mmol) and 1-Hydroxy benzotriazole (593 mg, 4.39 mmol) were added. Reaction mixture was stirred RT for 10 minutes followed by the addition of L-serine methyl ester hydrochloride (683 mg, 4.39 mmol) dissolved in DMF (5 ml) neutralized with triethylamine (0.6 ml, 4.39 mmol). The above reaction mixture was stirred at RT for 8 hours. DMF was distilled off under reduced pressure to give pale brown solid, which was taken in THF. DCU precipitated out and was filtered off. Water was added and the aqueous layer was extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated under vacuum. Crude compound was purified through precipitation using DCM and petroleum ether to yield 500 mg (39%) of the required compound as white solid. MS: ES (−): m/z 441(M−1); ES (+): m/z 443 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 9.342 (s, 1H), 9.109 (d; 1H), 8.633 (s, 1H), 8.161 (t, 1H), 7.369 (d, 2H), 7.676 (s, 1H), 7.619 (d, 2H), 7.242 (m, 1H), 7.066 (t, 1H), 7.024 (m, 1H), 5.149 (t, 1H), 4.575 (m, 1H), 3.821 (t, 2H), 3.657 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[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(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 2.34 g (12 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine, 2.23 g (12 mmol) of 4-nitrobenzoyl chloride, 1.94 g (15 mmol) of diisopropylethylamine and 70.5 mg of 4-(dimethylamino)pyridine in 25 ml of dichloromethane is stirred at room temperature for 2 hours, refluxed for 3 hours and allowed to stand at room temperature for 2 days. The mixture is washed with water, 1N sodium bicarbonate, water, 1N HCl, brine and dried (Na2SO4). The solvent is removed to give 4.0 g of solid. Trituration with ethyl acetate and filtering gives 2.85 g of off-white crystals, m.p. 185°-188° C.