Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: N#Cc1cccnc1Cl
Product: COc1cc(F)ccc1-c1ncccc1C#N
Yield: 85 %

Procedure:
Prepared in 85% yield from 2-chloronicotinonitrile and 2-fluoro-6-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 6.82-6.88 (m, 2H), 7.38-7.46 (m, 2H), 8.07 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[C:29]=3[F:37])[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:38])[C@@H:14]([OH:39])[C@@H:13]1[OH:40])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C@@H:12]1[C@@H:13]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:14]([O:39][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:38][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[C:29]=3[F:37])[CH:21]=2)([O:18][CH3:19])[O:17]1)([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
To a suspension of sodium hydride (24.0 g, 0.6 mol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (150 mL) was added a solution of (2S,3R,4S,5S,6R)-6-[[tert-butyhdimethyl) silyl]oxymethyl]-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 21i (49.5 g, 86 mmol) in anhydrous tetrahydrofuran (400 mL) slowly at 0° C. The mixture was stirred at 0° C. for 1 hour, and then benzyl bromide (81 mL, 690 mmol) was added. The mixture was warmed up to room temperature and further stirred for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (1000 mL) and extracted with ethyl acetate (300 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21j as yellow oil (72.7 g, 100%). This material was not further purified.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]#[CH:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH2:35][CH2:36][NH:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:30]=[CH:29]4)=[N:22][CH:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH2:35][CH2:36][N:37]([CH2:38][CH:39]3[CH2:40][CH2:41]3)[CH2:10][C:9]#[CH:8])[CH:30]=[CH:29]4)=[N:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: C#CCBr
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN(CCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21)CC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
45 mg (0.33 mmol) K2CO3 and 13 μL (0.18 mmol) 3-bromo-propyne are added at RT to a solution of 70 mg (0.16 mmol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 2 mL DMF and the reaction mixture is stirred for 4 h at RT. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (Alox, cyc/EtOAc 4:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O:11][CH3:12])=[O:10]
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Nc2ccc(C)cc2)cc1

Procedure:
p-toluidine (0.20 moles), p-carbomethoxybenzaldehyde (0.20 moles), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) were azeotropically refluxed in toluene (150 cc.). The required amount of water had been removed after 3 hours. The solvent was removed on the rotary evaporator and the residue was recrystallized with 95% ethanol to yield N-(p-carbomethoxybenzylidene)-p-methylaniline.
Reaction SMILES: [Cl-].[F:2][CH2:3][C@@H:4]([NH3+:24])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>CN(C)C=O>[Cl:34][CH:35]([Cl:39])[C:36]([NH:24][C@H:4]([CH2:3][F:2])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1)=[O:37]
Reactant: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@H]([NH3+])CF)cc2)on1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)on1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
To a dimethylformamide (3 ml) solution of (1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-aminium chloride (150 mg, 0.40 mmol) is added diisopropylethylamine (0.255 g, 2 mmol). After cooling the reaction mixture to 0° C. dichloroacetyl chloride (62 mg, 0.42 mmol) is added. The reaction is stirred at 0° C. for twenty minutes then quenched by the addition of water (1 ml). The reaction mixture is concentrated to a volume of approximately two milliliters and subjected to reverse phase HPLC purification to give the title compound (95 mg): 1H NMR (400 MHz, CDCl3) 3.06 (s, 3H) 4.30-4.43 (m, 1H) 4.49 (d, J=6.32 Hz, 2H) 4.56-4.67 (m, 2H) 4.93 (m, br, 1H) 5.19-5.24 (m, 1H) 5.87 (s, 1H) 6.61 (s, 1H) 7.03 (d, J=9.09 Hz, 1H) 7.52 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); m/z (CI) 454, 456, 458 ([M+H]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:27]=[C:26]([NH2:28])[C:6]2[NH:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1.[CH3:31][C:32]([CH3:38])([CH2:36][OH:37])[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:37][CH2:36][C:32]([CH3:38])([CH3:31])[C:33]([NH:28][C:26]1[C:6]2[NH:7][C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:9][C:5]=2[CH:4]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:27]=1)=[O:34]
Reactant: CC(C)(CO)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)C(=O)Nc1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a 25-mL, round-bottom flask was added 5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-amine (108 mg, 0.25 mmol, Example 58), 2,2-dimethyl-3-hydroxypropionic acid (47 mg, 0.4 mmol, Aldrich), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.4 mmol, Aldrich) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 36 h, washed with satd aq. NaHCO3 solution (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 531 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:3]=1[CH3:20].C=O.Cl.[CH3:24]NC>O1CCOCC1>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:14](=[O:19])[C:15](=[CH2:24])[CH2:16][CH2:17][CH3:18])[C:3]=1[CH3:20]
Reactant: CNC
Reactant: CCCCC(=O)c1cc2oc(C(=O)O)cc2c(C)c1C
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: C=C(CCC)C(=O)c1cc2oc(C(=O)O)cc2c(C)c1C

Procedure:
A mixture of 4,5-dimethyl-6-valerylbenzofuran-2-carboxylic acid (15 g.) paraformaldehyde (3.5 g.) and dimethylamine hydrochloride (7 g.) in p-dioxane (100 ml.) is refluxed for 8 hours and cooled. The 4,5-dimethyl-6-[(2-dimethylaminomethyl)valeryl]benzofuran-2-carboxylic acid hydrochloride which separates is filtered, dried, and dissolved in acetic acid (200 ml.) containing sodium acetate (20 g.). The reaction mixture is refluxed for two hours then poured into water (250 ml.) containing hydrochloric acid (25 ml.) affording 4,5 -dimethyl-6-(2-methylenevaleryl)-benzofuran-2-carboxylic acid which melts at 172° after recrystallization from butyl chloride.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1ccccc1OCCCBr
Product: COc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.786 g of 1-(3-bromopropoxy)-2-methoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=4.91.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1-(ethylsulfonyl)-4-fluorobenzene (1.36 mmol, 0.257 g) in sulfuric acid (1.32 ml) was added potassium nitrate (0.243 g) at 80° C. The mixture was stirred at 90° C. for 2 hours. Ice water (5 ml) was added and the mixture was extracted with ethyl acetate (25 ml) and washed with water (20 ml) and brine (10 ml). The organic extracts were combined and dried over sodium sulfate and concentrated. The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol. HPLC indicated 98% purity, mp 128-131° C., (0.21 g, 66% yield). 1H NMR (CDCl3): 1.35 (t, 3H, CH3), 3.21 (q, 2H, CH2), 7.55 (t, 1H, Ar—H), 8.21 (m, 1H, Ar—H), 8.64 (d, 1H, Ar—H); MS: 229 M−. Elemental Analysis (C, H, N, F, S) for C8H8FNO4S; calculated C, 41.20; H, 3.46; N, 6.01; F, 8.15; S, 13.75. found C, 41.31; H, 3.35; N, 5.85; F, 8.17; S, 13.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:23][OH:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 97.6 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid (1.23 g, 0.00381 mol) was allowed to react with hydroxylamine hydrochloride (0.2994 g, 0.00431 mol) in the presence of sodium carbonate (0.4567 g, 0.00431 mol) in absolute ethanol (20 mL) to give 1.257 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 165.5-166.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12OCCC[O:22]1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:34][N:35]=[C:16]3[C:15](=[O:22])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Reactant: N#CC1(CCl)CCCC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCC3)CN12

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 416[M−H]. m.p.: 171.2-171.9° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1COC[CH2:4]1.[OH:8][C:9]1[C:14](/[CH:15]=[CH:16]/[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:18](=[O:20])[CH3:19].C(Cl)(=O)C>O>[CH3:3][C:4]1[O:8][C:9]2[C:10]([C:18](=[O:20])[CH:19]=1)=[CH:11][CH:12]=[CH:13][C:14]=2/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/c1cccc(C(C)=O)c1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)Cl
Product: C/C=C/c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
12.52 g (313.2 mmol) of 60% sodium hydride (suspension in mineral oil) are introduced into 300 ml of absolute THF under argon at 10° C. 18.4 g (104.4 mmol) of 1-{2-hydroxy-3-[(1E)-prop-1-en-1-yl]phenyl}ethanone are slowly added dropwise to the suspension. After 15 min, 9 g (114.9 mmol) of acetyl chloride are added. The reaction mixture is stirred at room temperature overnight. Hydrolysis is carried out with 300 ml of water, and the mixture is extracted several times with ethyl acetate. Washing of the organic phase with saturated sodium chloride solution is followed by drying over sodium sulfate. The solvent is then removed in vacuo. The residue is taken up in 200 ml of methanol and heated with 50 ml of 20% strength hydrochloric acid at 80° C. for 30 min. The solvent is then removed in vacuo, and the residue is mixed with 400 ml of water. Several extractions with dichloromethane are carried out. After the organic phase has been dried over magnesium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 98:2). 10.5 g (50.2% of theory) of the title compound are obtained as a yellow oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH:11]([F:13])[F:12])[N:6]=1)C.Cl>O>[F:13][CH:11]([F:12])[C:7]1[N:6]=[C:5]([CH:4]=[O:3])[N:9]([CH3:10])[N:8]=1
Reactant: CCOC(OCC)c1nc(C(F)F)nn1C
Agent: Cl
Solvent: O
Product: Cn1nc(C(F)F)nc1C=O
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Water (190 mL) was added to 5-(diethoxymethyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole (47.6 g, 0.2024 mol, from Step 2), and the mixture was degassed. Then concentrated HCl (73 mL, 0.81 mol, 11.1 M) was added, and the mixture was stirred at 55–60° C. for 24 h. After this, the reaction mixture was evaporated, and the residue was repeatedly (8–10 times) evaporated with THF until the water and HCl were completely removed. The final residue was distilled under vacuum to give the crude title product (bp 46–50° C. at 0.04 mm Hg), containing, according to LC-MS data, 7% of a dimerization side-product. Further purification on a silica gel (ethyl acetate/hexane 1:3) yielded 18.37 g (56.3%) of 3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole-5-carbaldehyde. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, CDCl3): δ 4.25 (s, 3H), 6.74 (t, J=56 Hz, 1H), 10.01 (s, 1H). LC/MS (API-ES) calcd for C5H5F2N3O: 161.04, found (M+H+): 162.1; (M+18+H+): 180.1 m/z.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Yield: 105.8 %

Procedure:
A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (27 g, 160 mmol, 1.6 equiv), 3,6-dichloropyridazine (15 g, 100 mmol, 1.0 equiv) and K2CO3 (42 g, 302 mmol, 3.0 equiv) in isopropanol (15 mL) was stirred at 100° C. for 36 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was dried over Na2SO4 and concentrated in vacuo. Partial purification over silica gel using a 30-75% gradient of EtOAc/hexanes gave the desired product (29.6 g, 103%) which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:18]1[C:23]([NH2:24])=[CH:22][C:21]2[O:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[O:28][C:20]=2[CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:30][C:27]1([F:29])[O:28][C:20]2[CH:19]=[CH:18][C:23]([NH:24][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)=[CH:22][C:21]=2[O:25][C:26]1([F:31])[F:32]
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)OC(F)(F)C(F)(F)O4)n2)c1
Yield: 10.4 %

Procedure:
Following Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 2,2,3,3-tetrafluoro-6-amino-1,4-benzodioxene (78.1 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. Evaporation under vacuo followed. The resulting solid was washed with 50 mL dichloromethane and filtered. The insoluble solid was dissolved in 3 mL of hot ethyl acetate. When this mixture was allowed to cool down in the freezer some crystals appeared. Filtration and washing with 2 mL of cold ethyl acetate gave 10.8 mg of the title compound. Yield: 10.4%. 1 H NMR (250 MHz, DMSO-d6) δ 2.08 (s, 3 H), 7.44 (d, 1 H, J=9.1 Hz), 7.47 (d, 1 H, J=7.8 Hz), 7.59 (bd, 1 H, J=7.6 Hz), 7.704-7.759 (m, 2 H), 7.96 (d, 1 H, 2.4 Hz), 8.21 (s, 1 H), 8.45 (bs, 1 H), 8.51 (s, 1 H), 9.95 (s, 1 H), 10.10 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.00, 106.13, 115.92, 117.34, 118.01, 120.13, 121.08, 129.31, 130.04, 130.98, 133.62, 136.16, 136.79, 139.03, 139.99, 147.90, 150.84, 168.40; m/z 435.1 [(M+H)+, calcd for C20H14F4N4O3 434.1].
Reaction SMILES: [CH2:1]([OH:8])[CH:2]1[CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:8][CH2:1][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CC=CCC1
Reaction time: 20 h
Yield: 99.8 %

Procedure:
To a stirred solution of 1,2,3,6-tetrahydrobenzylalcohol (1) (1.12 g, 10 mmol) and imidazole (1.36 g, 20 mmol) in DMF (10 mL) was added TBDMSCl (1.81 g, 12 mmol). After 20 hours, the mixture was treated with brine (100 mL) and the product was extracted with hexanes (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo to give compound (2) (2.26 g, 100%) as colorless liquid. Rf0.29 (hexanes). 1H NMR (CDCl3) δ 5.65-5.64 (m, 2H), 3.48 (d, J=2.3 Hz, 1H), 3.45 (d, J=2.3 Hz, 1H), 2.08-2.00 (m, 3H), 1.82-1.66 (m, 3H), 1.32-1.19 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 127.04, 126.23, 67.95, 36.34, 28.23, 25.97, 25.70, 25.33, 24.78, 18.38, −5.32.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].Cl[C:23](=[O:29])[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:23](=[O:29])[C:24]([OH:26])=[O:25]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Triethylamine (2.28 mL; 16.22 mmol) was added to the mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.53 g; 6.49 mmol) and ethyl 2-chloro-2-oxoacetate (0.815 mL; 7.14 mmol) in dichloromethane (50 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes and washed with an aqueous solution of sodium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. Ethanol (2 mL) and water (7.5 mL) were added to the resulting residue, followed by a 2M solution of sodium hydroxide (9.5 mL, 19 mmol). The mixture was stirred at room temperature for 20 minutes and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The precipitate was collected, and was dissolved in ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and was evaporated to dryness to give 1.36 g (81%) of 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetic acid as a yellowish solid.
Reaction SMILES: [CH:1]([C:12]([O:14]CC)=O)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:12]([CH:1]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: NCc1ccc(Cl)cc1
Product: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Yield: 30.5 %

Procedure:
Triethyl methanetricarboxylate (2.32 g) and 4-chlorobenzylamine (1.42 g) are stirred at room temperature for 16 h. Insoluble material is filtered off and the filtrate is purified by column chromatography (hexanes/acetone, 5/1) to give 1 g (12%) of the title compound as an oil which slowly solidifies. Physical characteristics: MS (ESI+) m/z 330 (M+H)+. 1H NMR (CDCl3) δ7.70, 7.31, 7.26, 4.48, 4.38, 4.28, 1.30.