Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: OBO
Product: O=Cc1cccc(-c2ccccc2C(F)(F)F)n1

Procedure:
6-(2-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (2-(trifluoromethyl)phenyl)boronic acid (43.5 mg, 135.1 mg theoretical, 32.2%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:7][C:8](=[O:23])[CH:9]([NH:19][C:20](=[O:22])[CH3:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=O)[CH3:6].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:5]([O:7][C:8]([C:9]1[N:19]=[C:20]([CH3:21])[O:22][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:23])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1-c1cccc(F)c1

Procedure:
At 0° C. SOCl2 (0.88 mmol) is added to a stirred solution of 2-acetylamino-3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (0.63 mmol) in CHCl3 (0.38 mL). After 30 min the mixture is heated to reflux for 60 min. An additional portion of SOCl2 (0.16 mmol) is added and the mixture is heated to reflux for further 60 min. An aq. K2CO3 solution (1.0 M) is added, the layers are separated and the aq. layer is extracted twice with ether. The combined organic layers are washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the desired ester which is used without further purification. LC-MS: tR=0.93 min; [M+H]+=250.3.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:4]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Ic1n[nH]c2ncncc12
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
569 mg (2.313 mmol) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 828 mg (2.544 mmol) of caesium carbonate were initially charged in 10 ml of DMF, and 481 mg (2.544 mmol) of 2-fluorobenzyl bromide dissolved in 2 ml of DMF were added. The reaction mixture was stirred at RT overnight, diluted with 50 ml of water and filtered with suction, and the residue was dried under high vacuum. 733 mg of the target compound were obtained (purity 83%; 74% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][O:11][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-D-serinamide (1, 1.93 g, 7.78 mmol) and imidazole (1.21 g, 17.81 mmol) in DMF (9 ml) stirred under N2 at room temperature, was treated with neat tert-butyl(chloro)diphenylsilane (2.2 ml, 8.56 mmol) and further stirred for 17 h. Diluted with EtOAc, washed with 5% KHSO4 in water, then sat NaHCO3, dried over Na2SO4, filtered and concentrated. Purified through a chromatographic cartridge of silicagel (50 g) eluted with 10% to 60% EtOAc in hexane to give 3.55 g (94% yield) of title compound as colorless oil. MS: m/z=509.2 (MNa+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]CC(C)C)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.CCOCC.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)COC(=O)c1cccc2c(Br)cccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][F:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:16][C@@H:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][F:15])/[C:8]([NH:16][C@@H:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]23)=[O:10])[N:6]=1
Reactant: Nc1nc(/C(=N/OCCF)C(=O)O)cs1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-(2-fluoroethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the above-identified compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Cl-].[Li+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1)[CH:12]=[CH2:11]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(Cl)c1

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (22 mg, 1.0 mmol), allyl tri-n-butylstannane (400 mg, 1.2 mmol), lithium chloride (126 mg, 3.0 mmol), and Pd(PPh3)4, (18 mg, 0.04 mmol) in toluene (10 mL), was refluxed overnight. Then the reaction was quenched with aq. KF (10 mL), extracted with ethyl acetate (10 mL×3), dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography to give the title product.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C@@H:25]1[O:27][CH2:26]1)[Cl:24]>ClCCCl>[Cl:24][CH2:23][C@H:25]([OH:27])[CH2:26][N:14]1[CH:15]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:13]1[CH2:12][CH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[N:8]=1
Reactant: Cc1cccc2nc(CCc3nc(-c4cccs4)c[nH]3)nn12
Reactant: ClC[C@H]1CO1
Solvent: ClCCCl
Product: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CCl)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 5-Methyl-2-[2-(4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (48 mg, 0.16 mmol) in 1,2-dichloroethane (1.5 mL) was added (R)-(−)-epichlorohydrin (80 μL, 1.00 mmol), the reaction vessel was capped and stirred at 100° C. for 16 hours. The volatiles were removed in vacuo and the residue purified by preparative LC-MS to yield the title compound. 6% yield, LC-MS: m/z=402.1 (MH+), tR=0.49 minutes, method B.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1.O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg, 0.64 mmol) dissolved in 750 uL pyridine was added 4-tert-butylbenzenesulfonyl chloride (225 mg, 0.97 mmol) and the mixture stirred at 60° C. overnight. The reaction mixture was diluted with 1.0 mL H2O and the precipitate formed was collected by vacuum filtration. The crude product was recrystallized from EtOAc/hexane yielding 190 mg of pure title compound. 1H NMR (CDCl3) δ 9.87 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.33-7.31 (m, 3H), 1.22 (s, 9H). MS: m/z=429.0 (M++1).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC=CC=1.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)[CH:20]=2)[NH:15][CH:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][NH:2][C:3]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:18][CH:17]=2)[C:13]([CH3:12])=[CH:14]1)=[O:4]
Reactant: CNC(=O)Oc1ccccc1
Reactant: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)n1cc(C)c2cc(Oc3ccnc(N)c3)ccc21
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
Phenyl N-methylcarbamate (350 mg, Production example 2-1) was added to a solution of 4-(3-methyl-1H-5-indolyl)oxy-2-pyridinamine (500 mg), sodium hydride (93 mg) and N,N-dimethylformamide (5 ml) at room temperature; and the reaction mixture was stirred for 2 hours and 45 minutes. Water was added to the reaction mixture; extraction was performed with ethyl acetate; and purification was performed by NH-silica gel column chromatography (Fuji Silysia, hexane:ethyl acetate=1:2, sequentially, ethyl acetate) to yield the title compound as a pale yellow amorphous solid (365 mg).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=3[N:19]=2)=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9]2.Cl.C[N:32](C)CCCN=C=NCC>O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27]([NH2:32])=[O:28])=[CH:26][C:20]=3[N:19]=2)=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:15])[F:16])[CH:10]=[CH:9]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(-c2nc3cc(C(=O)O)ccc3[nH]2)c2ccc(C(F)(F)F)nc12
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)c2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
Ammonia (0.5M in 1,4-dioxane, 3.9 ml) was added to a stirred solution of 2-(8-methoxy-2-trifluoromethylquinolin-5-yl)-1H-benzimidazole-5-carboxylic acid (0.15 g) in 1,4-dioxane (30 ml) at room temperature under an inert atmosphere. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) was added followed by 4-dimethylaminopyridine (36 mg) and the reaction stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (2×40 ml) and water (50 ml). The combined organic phases were dried over magnesium sulphate and preadsorbed onto silica in vacuo. Purification by column chromatography eluting with 10% methanol in ethyl acetate afforded the title compound as a cream solid (20 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CCCCCC.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccn3)C(C)(C)O4)CC2)cc1
Yield: 86 %

Procedure:
Using 2-chloromethylpyridine hydrochloride and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 86%. mp. 120–121° C. (hexane-ethyl acetate). 1H-NMR (CDCl3) δ: 1.37 (3H, s), 1.59 (3H, s), 2.09 (3H, s), 2.25 (3H, s), 2.28 (3H, s), 3.05–3.28 (8H, m), 3.79 (3H, s), 4.67 (2H, s), 4.75 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.15–7.21 (1H, m), 7.48 (1H, d, J=7.6 Hz), 7.68 (1H, t, J=7.6 Hz), 8.52 (1H, d, J=4.4 Hz).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[NH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1>CC(N(C)C)=O>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=1
Reactant: Nc1ccc(I)cn1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccccc2)cn1

Procedure:
3.3 G. of potassium phenolate, 5.47 g. of 2-amino 5-iodopyridine and 1.78 g. of cuprous oxide in 150 ml. of dimethylacetamide are heated at reflux under a nitrogen atmosphere for 24 hours. The solvent is removed in vacuo and the residue is extracted with chloroform. Chromatography of the methylene chloride soluble portion with silica gel and elution with ethyl acetate yields 2-amino-5-phenoxy pyridine m.p. 67°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[C:9]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: [H][H]
Reactant: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: OCCCOc1c(Cl)cc(O)cc1Cl
Yield: 93.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 1, by the treatment of 11.8 grams (0.036 mole) of 3-[2,6-dichloro-4-(phenylmethoxy)phenoxy]propan-1-ol with hydrogen gas in the presence of a catalytic amount of 10% palladium on carbon in ethanol using a Parr hydrogenation apparatus. Following the theoretical uptake of hydrogen, the reaction mixture was and filtered and concentrated under reduced pressure to a residue, yielding 8.0 grams of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.B#B.O>O1CCCC1>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) in tetrahydrofuran (100 ml) at 0° C. was added diborane (70 ml, 1.0 M solution in tetrahydrofuran). The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled to 0° C. and water was added dropwise (50 ml). The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-60% ethyl acetate/hexane) to give 3-(2-hydroxyethyl)bromobenzene (9.0 g).
Reaction SMILES: [F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[N:6]=1.[Cl-].[NH4+]>CCO.O.[Zn]>[F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH:11]=2)[NH2:17])[N:6]=1
Reactant: Cc1ccc(-c2noc(C3CC3F)n2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2noc(C3CC3F)n2)cc1N
Temperature: 85 °C

Procedure:
To a suspension of 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (129) (162 mg, 0.62 mmol) in EtOH:H2O (4:1) (3.3 mL) was added zinc dust (161 mg, 2.46 mmol) and ammonium chloride (132 mg, 2.46 mmol). The reaction mixture was heated at 85° C. for 24 hours, then filtered hot over celite and rinsed with ethyl acetate. The solvent was concentrated to give 5-(5-(2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (130).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([S:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[CH3:22][S:21][C:15]1[CH:20]=[CH:19][C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a cold (0° C.) solution of phenylacetyl chloride (92.8 g, 0.6 mol) in CHCl3 (1.2 L) was added AlCl3 (80 g, 0.6 mol) in portions. Thioanisole (62.1 g, 0.5 mol) was then added dropwise. The resulting mixture was stirred at r.t. for 1.5 h. The mixture was poured into 4 L of ice and extracted with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was slurried in 300 mL of 20 % EtOAc/hexane, filtered and washed with hexane to give 78 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[Si:35]([O:34][CH2:33][C:32]([CH3:43])([CH3:42])[CH2:31][N:6]1[C:7](=[O:28])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:29]=[C:5]12)([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:36])[CH3:37]
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (4.7 mL), cesium carbonate (8.1 g) and N,N-dimethylacetamide (50 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[CH2:35]Br>CN(C=O)C>[Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[N:15]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([C:40]([F:41])([F:42])[F:43])=[C:32]([F:31])[CH:33]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: O=S(=O)(Nc1nc2ccc(C(F)(F)F)cn2c1Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(C(F)(F)F)c(F)c1)c1nc2ccc(C(F)(F)F)cn2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of compound 9-E (0.015 g, 0.025 mmol) in DMF (2.0 mL) was added Na2CO3 (0.011 g, 0.099 mmol) and 3-fluoro-4-trifluoromethylbenzyl bromide (0.006 g, 0.025 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2) eluting with a gradient of 0-100% ethyl acetate in hexane to afford Compound 60 (0.008 g, 58%); MS m/z (M+H+) 552.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1)=[N+:16]=[N-:17]
Reactant: Clc1ccc2[nH]cc(CCCBr)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1c[nH]c2ccc(Cl)cc12

Procedure:
A mixture of 3-(3-bromopropyl)-5-chloro-1H-indole (0.730 g; 2.68 mmol) and sodium azide (0.522 g; 8.03 mmol) was stirred in DMF (5 mL) for 18 hours and was then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. After separation, the organic layer was dried over magnesium sulfate and the volatiles were evaporated under reduced pressure to give quantitatively 3-(3-azidopropyl)-5-chloro-1H-indole as an oily residue which was used without purification in the next step.