Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[CH:5]2.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1>[CH3:20][O:19][C:3]1[C:2]([CH:29]=[O:30])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1c(Br)ccc2c1cnn2COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)ccc2c1cnn2COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a stirred solution of 5-bromo-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-indazole (179 mg, 0.50 mmol) in THF (5.0 mL) at −78° C. under a nitrogen atmosphere was added n-butyl lithium (2.5 M in hexanes, 220 μL, 0.55 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour and then DMF (78 μL, 1.0 mmol) was added. The mixture was stirred at −78° C. for 30 min, then allowed to reach RT and stirred for a further 1 hour. The reaction mixture was quenched with water (5 mL), separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (78 mg, 51%). LCMS (Method B): RT=4.55 min, [M+H]+=307.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=4)[O:30][C:29]3=[O:45])=[N:19][C:20](S(C)(=O)=O)=[N:21][CH:22]=2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1.Cl.[F:47][CH:48]1[CH2:51][NH:50][CH2:49]1.Cl>C(OCC)(=O)C.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH2:27][N:28]3[C@@H:32]([CH3:33])[C@@H:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=4)[O:30][C:29]3=[O:45])=[N:19][C:20]([N:50]3[CH2:51][CH:48]([F:47])[CH2:49]3)=[N:21][CH:22]=2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: FC1CNC1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
Triethylamine (0.499 mL, 3.58 mmol) was added to a THF (5 mL) solution of (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-5-[3-(trifluoromethoxy)phenyl]-1,3-oxazolidin-2-one (Step A, 410 mg, 0.716 mmol) and 3-fluoroazetidine hydrochloride (300 mg, 2.69 mmol). The reaction was placed in an oil bath and heated for 20 minutes at 60° C. LCMS showed complete conversion to product. The reaction was diluted with ethyl acetate (50 mL) and poured into 0.1N HCl solution (50 mL). The ethyl acetate layer was washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated on rotary evaporator. The crude isolate was purified by silica gel chromatography, eluting with a 0-50% ethyl acetate/hexanes linear gradient followed by a hold at 50% ethyl acetate/hexanes to give the title compound as a pale yellow solid. LCMS (M+H)+: 568.3. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J=2.3 Hz, 1H), 8.14 (s, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.25 (m, 2H), 7.15 (s, 1H), 5.59 (d, J=8.4 Hz, 1H), 5.55 (m, 0.5H), 5.44 (m, 0.5H), 4.66 (d, J=17.1 Hz, 1H), 4.61 (m, 2H), 4.43 (m, 2H), 4.32 (m, 1H), 4.03 (d, J=17.5 Hz, 1H), 3.96 (s, 3H), 0.75 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:28][NH:27][C:22]([C:20]1[CH:19]=[N:18][C:14]2[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13]=2[CH:21]=1)=[NH:23]
Reactant: NO
Reactant: N#Cc1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Temperature: 80 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a suspension of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (75 mg, 0.203 mmol) in ethanol (2 mL) and water (0.5 mL) was added hydroxylamine hydrochloride (42.3 mg, 0.609 mmol) and sodium carbonate (108 mg, 1.015 mmol). The reaction was heated to 80° C. and stirred at that temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting paste was suspended in water (10 mL) and extracted with EtOAc (2×20 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide N-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboximidamide (80 mg, 0.199 mmol, 98% yield) as a white solid, which was used without further purification. LCMS (+ESI) m/z=403.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: NCCS
Reactant: Cc1cn2c(Cl)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2c(SCCN)cccc2n1
Yield: 53.1 %

Procedure:
To a suspension of cysteamine hydrochloride (2.95 g, 26 mmoles) in ethanol (100 ml) was added 60% sodium hydride (oily; 2.08 g, 26 mmoles) with stirring under ice-cooling and the mixture was stirred for 5 minutes. 5-chloro-2-methylimidazo[1,2-a]pyridine (3.33 g, 20 mmoles) was added to the mixture, followed by heating at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with 1N-NaOH and dried over anhydrous potassium carbonate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate/ethanol/triethylamine=6:2:1) to obtain 2.2 g of the desired product (53.6%, brown oily product).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][NH2:4].[O:6]=[C:7]1[NH:15][CH:14]=[N:13][C:12]2[N:11]([CH2:16][CH2:17][C:18](OCC)=[O:19])[CH:10]=[N:9][C:8]1=2>C(#N)C>[O:6]=[C:7]1[NH:15][CH:14]=[N:13][C:12]2[N:11]([CH2:16][CH2:17][C:18]([NH:4][CH2:3][CH:2]([OH:5])[CH3:1])=[O:19])[CH:10]=[N:9][C:8]1=2
Reactant: CC(O)CN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: CC(O)CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.500 g (6.66 mmol) DL-1-amino-2-propanol and 0.250 (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated together in a 10 ml round bottom flask with stirring at 120° C. for one hour. The solution was allowed to cool to room temperature and 10 ml acetonitrile was added and the solution was stirred. The solution was triturated with a small amount of methanol (approximately 1 ml) and was stirred until the appearance of a fine white precipitate. The solution was filtered and the white solid was washed with acetonitrile and then with ether. Upon drying, 240 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-hydroxypropyl)propanamide (AIT-0059) as a white solid was obtained. Yield: 85%. m.p. -212°-216° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[N+:18]([C:21]1[CH:22]=[C:23]([CH2:27]Br)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:27][C:23]1[CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A stirred solution of 3.8 grams (0.026 mole) of 2-naphthol and 3.6 grams (0.026 mole) of potassium carbonate in 200 mL of acetone was heated at reflux for about 30 minutes. The reaction mixture was then cooled to ambient temperature, and 5.0 grams (0.023 mole) of 3-nitrophenylmethyl bromide was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then warmed to reflux where it stirred for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and an aqueous solution saturated with sodium bicarbonate. The organic layer was separated and washed with three 50 mL portions of an aqueous solution saturated with sodium bicarbonate and then with one 50 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to a residue. The residue was crystallized with hexane, yielding about 4.5 grams of 3-(naphth-2-yloxymethyl)nitrobenzene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:22])[CH:17]([O:20][CH3:21])[O:18][CH3:19])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:22])[CH:17]([O:18][CH3:19])[O:20][CH3:21])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: COC(OC)C(C)Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C(OC)OC)ncn1
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.3 ml of a solution containing 0.05 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.3 ml of a solution containing 0.16 g of 4-chloro-6-(2,2-dimethoxy-1-methylethoxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 1 hour and further stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.11 g of 4-(2-butynyloxy)-6-(2,2-dimethoxy-1-methylethoxy)pyrimidine (the present compound (18)).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].N#N.[O:7]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:8]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:8][CH:9]([OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: OCCCCCCCCCCCCCCC1CO1
Reactant: NCCO
Agent: N#N
Solvent: CCO
Product: OCCCCCCCCCCCCCCC(O)CNCCO
Yield: 66.7 %

Procedure:
A 50-ml two-necked flask equipped with a stirrer, dropping funnel and N2 inlet tube was charged with 4.14 g (68 mmol) of ethanolamine and 0.8 g of ethanol. While heating and stirring the mixture at 80° C. in an N2 atmosphere, an ethanol solution of 0.87 g (3.4 mmol) of 1,2-epoxy-16-hexadecanol was added dropwise over 1.5 hours. The resultant mixture was stirred further for 2 hours at 80° C. After completion of the reaction, ethanol and excess ethanolamine were distilled off under reduced pressure, and the resultant residue was purified by flash column chromatography on silica gel, thereby obtaining 0.72 g (yield: 68%) of the title compound (IId-1).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.CC(C1C=CC(Cl)=CC=1)=O.C(OC(=O)C(OCC)=O)C.C([N-]C(C)C)(C)C.[Li+].Cl.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][NH2:57])=[CH:52][CH:51]=1.C1(N2C=CC(C3C=CC=CC=3)=N2)C=CC=CC=1>CCO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:56]([C:53]3[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=3)[N:57]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 18 h

Procedure:
Ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate sodium salt (10.0 g, 36.1 mM), synthesized from 4-chloroacetophenone and diethyloxalate employing lithiumdiisopropylamide as base, and 4-methoxyphenylhydrazine hydrochloride (6.31 g, 36.1 mM) in cold absolute EtOH (360 ml) were stirred at 0° for 4hr., at rt for 18 hr and then at reflux for 5 hr. The resulting solution was evaporated in vacuo, H2O (100 ml) was added and the aqueous phase extracted with Et2O (3×100 ml). The combined ether layerwas washed (brine), dried (Na2SO4) and concentrated in vacuo to give a crude solid which by NMR was a 5:1 mixture of the title compound tothe corresponding 1,3-diphenyl pyrazole. Recrystallization from EtOAc:hexane (2×) afforded pure 1 (7.93 g, 61%) as a white solid, mp=107°-108° C., MS, (DCI) m/e 357 (M+1).
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][N:2]=1.[H][H]>[Ni].C(O)C>[CH2:1]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: C1=NCCCC12CCCCC2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: C1CCC2(CC1)CCCNC2
Yield: 88.1 %

Procedure:
A solution of 2-azaspiro-[5.5]-undec-1-ene (15 g.; 0.10 mole) and one teaspoon (3 g.) of W2 Raney nickel catalyst in absolute ethanol (300 ml.) is hydrogenated at an initial pressure of B 40 psi until hydrogen uptake ceases (2 hours). The mixture is filtered through celite and the filtrate concentrated under reduced pressure. Distillation of the residual liquid yields 88% of 2-azaspiro-[5.5]-undecane (13.5 g.), b.p. 55°-57° C./0.10 mm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24].[OH-].[Na+]>CN(C)C=O>[C:11]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#CCCCCCCBr
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCCCCCCC#N)cc(C(C)(C)C)c1
Temperature: 120 °C

Procedure:
A mixture containing 20.6 g (0.10 mole) of 3,5-di-t-butylphenol, 20.9 g (0.11 mole) of 7-bromoheptanenitrile, 4.0 g (0.10 mole) of sodium hydroxide and 250 ml of dimethylformamide was heated at 120° C. for about forty hours. The solvent was evaporated and the residue was added to 250 ml of water. The resulting oil was separated and dissolved in 250 ml of diethyl ether. The ether solution was washed twice with 250 ml portions of 10% sodium hydroxide, washed once with 250 ml water, dried over magnesium sulfate, and evaporated to give an oil which solidified on standing. The solid was recrystallized twice from methanol. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.[Cl-].C(Cl)(=O)C([Cl:27])=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([Cl:27])=[O:17])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N(CCc1cccs1)CC(=O)Cl

Procedure:
2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (14 g, 54.41 mmol) was dissolved in dry dichloromethane (DCM) (300 mL). To this suspension was added 0.1 mL of DMF, followed by the careful addition of oxayl chloride (10.4 g, 81.93 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time 0.5 mL of additional oxalyl chloride was added. The solvent was evaporated under vacuum to give 2-(N-(ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetyl chloride. This acid chloride was re-dissolved in dry DCM (300 mL) and AlCl3 (18.1 g, 135.74 mmol) was added at room temperature. The reaction was kept at room temperature for 1 hour then quenched by the slow addition of ethanol (about 10 mL). The mixture was then poured into ice and stirred for 1 hr. The aqueous mixture was extracted with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to give a residue, which was purified by silica gel chromatography to produce ethyl 4,5,7,8-tetrahydro-4-oxothieno[3,2-d]azepine-6-carboxylate (7.4 g, 30.92 mmol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[C:7]([OH:9])=[O:8].[CH2:21](Br)[C:22]#[CH:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[C:7]([O:9][CH2:23][C:22]#[CH:21])=[O:8]
Reactant: C#CCOc1cc(C(=O)O)cc(Cl)c1OCC#C
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(Cl)c(OCC#C)c(OCC#C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Sodium hydride (0.23 g; 60% dispersion in mineral oil) was added to a solution of 3-chloro-4,5-dipropargyloxybenzoic acid (1.50 g) in N,N-dimethylformamide (50 ml) at 0° C., followed by stirring at room temperature for 1 hour. Propargyl bromide (0.80 g) was added thereto, and the resultant mixture was stirred at 90° C. for 5 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography using toluene as an eluent to give propargyl 3-chloro-4,5-dipropargyloxybenzoate (1.03 g). m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@@H](C=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To 16F (2.83 g, 8.44 mmol) in dichloromethane (60 ml) was added Dess-Martin periodinane (4.30 g, 10.13 mmol) at rt. The reaction was stirred at rt for 2 h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography (0-30% ethyl acetate/hexanes). The desired fractions were combined, concentrated to give 16G (2.0 g, 6.00 mmol, 71.1% yield) as colorless oil. MS (ESI) (m/z): 331.3, 333.3 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 9.72 (s, 1H) 7.40 (d, J=1.77 Hz, 1H) 7.24-7.38 (m, 6H) 6.95 (d, J=8.08 Hz, 1H) 4.46-4.61 (m, 2H) 4.02-4.16 (m, 2H) 3.67-3.81 (m, 1H) 2.34 (s, 3H).
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]2[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:17])=[CH:11][CH:10]=1>>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2)C(Cc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)cc1)N1CCNCC1Cc1cccnc1
Reaction time: 8 h
Yield: 86 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(4-chlorophenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate (105 mg, 0.193 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 67.0 mg (86%) of the desired product as an off-white solid. LC-MS: RT=3.66 min, [M+H]+=331.1.
Reaction SMILES: COC1C=C[C:6]([CH2:7][NH:8][C:9]2[N:14]=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=C(N)C=2)=C(F)C=1>C(Cl)Cl>[NH2:14][C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.4 %

Procedure:
2-(4-Fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.362 M, 0.351 mL, 0.127 mmol, 1.3 eq) was added to a solution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (0.022 g, 0.100 mmol, 1.0 eq) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred for 13 h at room temperature and then concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck gel 40-63 μM, 230-240 mesh, 1:1 ethyl acetate/hexane) to afford the title compound (0.025 g, 64%) as a solid. 1H NMR (CD3OD) δ 7.62-7.67 (m, 2H), 7.23-7.29 (m, 2H), 7.07-7.12 (m, 2H), 6.95-6.99 (m, 2H), 6.12-6.14 (m, 1H), 5.86-5.87 (m, 1H), 3.61 (s, 2H); MS (ESI+) m/z 399 (M+H)+; HRMS (ESI+) calcd.: 399.1269. found: 399.1269.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])(=O)CC.Cl>ClC1C=CC=CC=1Cl>[Cl:16][C:11]1[C:10]([OH:9])=[C:15]([C:10](=[O:9])[CH2:11][CH3:12])[CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)Oc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CCC(=O)c1cccc(Cl)c1O
Temperature: 115 °C
Reaction time: 3 h

Procedure:
Anhydrous aluminum trichloride (130 g, 0.974 mol) in 150 ml of dry o-dichlorobenzene is cooled to 10° C. and 2-chlorophenyl propionate (100 g, 0.543 mol) is added slowly dropwise to this reaction mixture (15 minutes). The flask with the mixture is heated slowly in an oil bath to 110-120° C. At this temperature, HCl begins to evolve. The temperature is then raised slowly to 130-140° C. and the reaction mixture is held within this temperature range for three hours. After the oil bath has been removed and the batch has cooled, the excess aluminum chloride is broken down by addition of 350 g of crushed ice, followed by the addition of 50 ml of concentrated hydrochloric acid. After the reaction mixture has cooled, ethyl acetate (500 ml) is added. The organic phase is separated off and washed with saturated sodium hydrogen carbonate solution (500 ml) and brine (500 ml). After the organic phase has been dried and the solvent has been removed on a rotary evaporator, the residue is purified by chromatography on silica gel (eluent: toluene). This isolates 10 g (10%) of the desired compound and also 40 g (40%) of the corresponding regioisomer, 5′-chloro-3′-hydroxy propiophenone.