Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[Cl:8][C:9]1[CH:10]=[C:11]([OH:30])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18]>>[Cl:8][C:9]1[CH:10]=[C:11]([O:30][CH2:2][C:3]2[N:7]=[CH:6][O:5][N:4]=2)[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)([OH:28])[C:17]([F:18])([F:20])[F:19]
Reactant: ClCc1ncon1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3ncon3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 3-(chloromethyl)-1,2,4-oxadiazole and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=429.3 (MH+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(OCc2cccc(F)c2)cc1
Reactant: ClCCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(COc2ccc(OCCCN3CCOCC3)cc2)c1

Procedure:
To a solution of 0.56 g (0.01 mol) of potassium hydroxide in 18 ml of absolute ethanol are added 2.18 g (0.01 mol) of 4-(3-fluorobenzyloxy)phenol. There is then added a solution of 1.64 g (0.01 mol) of N-(3-chloropropyl)morpholine in 2 ml of absolute ethanol. The mixture is stirred at reflux for 24 hours, allowed to cool and then refrigerated. The solid which forms is collected by filtration, washed with absolute ethanol and dissolved in diethyl ether. The ethereal solution is washed consecutively with water (20 ml), 10% aqueous sodium hydroxide (3×15 ml) and water until neutral to litmus. The solution is dried over sodium sulfate, filtered and evaporated and recrystallized from diethyl ether-petroleum ether and from diethyl ether alone to yield N-[3-(4-{3-fluorobenzyloxy}phenoxy)propyl]morpholine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Agent: Cl
Solvent: ClCCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 mL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1 N HCl. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted throughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ 0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([CH:26]=[N:27][OH:28])[C:10]=1[S:29]([CH3:31])=[O:30]>O1CCCC1>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]1[CH:9]=[C:10]([S:29]([CH3:31])=[O:30])[C:11]([CH:26]=[N:27][OH:28])=[N:12]1
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CS(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C=NO
Reaction time: 4.5 h
Yield: 12.5 %

Procedure:
Tert-butyl nitrite (1.25 g) was added to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in tetrahydrofuran and stirred for 4.5 hours. After evaporation the resulting orange solid was triturated with carbon tetrachloride to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.24 g) m.p.239-240° C. Compound 20.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:4][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)[N:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: C=CCNc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of of allylamine (0.447 mL, 5.96 mmol) and 2-bromo-6-[4-(trifluoromethyl)phenyl]pyridine (0.1 g, 0.298 mmol) in ethanol (5 mL) were heated at 100° C. in a 25 mL pressure vessel. After heating overnight the reaction was cooled and copper sulfate was added and heating continued at 100° C. overnight. After this time the reaction was allowed to coole to room temperature and concentrated in vacuo. Purification by SPE (Silica, 10 g) eluting 3:1 cyclohexane:chloroform afforded the title compound as a dark yellow solid (0.062 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[C:7]=1[Br:10]
Reactant: Cc1cc(N)cc(C)n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(N)c(Br)c(C)n1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A solution of 2,6-dimethylpyridin-4-ylamine (2.00 g, 16.4 mmol) in 5 mL of acetic acid was treated dropwise with a solution of bromine (0.84 mL, 16.3 mmol) in 2 mL of acetic acid at room temperature in a water bath over a period of 10 minutes. After I hour, the resulting slurry was treated with 40 mL of 20% sodium hydroxide solution and extracted with three 100 mL portions of dichloromethane (CH2Cl2). The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid (starting material-desired product-dibromo byproduct (1:3:1)) was dissolved in 100 mL of hot hexanes and hot filtered to remove the insoluble starting material. The filtrate was allowed to cool to room temperature, which gave the title product as fine white needles (1.30 g, 40% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1.O>CN(C)C=O>[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCC4=O)cc3C)CC2)c(C)c1
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
Pyrrolidin-2-one (322 mg) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (159 mg) was added, and the mixture was stirred for 30 min. To the reaction mixture was further added [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (620 mg) described in Preparation Example 146, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[N:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1ccccc1CO
Yield: 81.8 %

Procedure:
A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:35])[NH:14][C:15]3[N:20]=[C:19]([O:21][CH2:22][CH:23]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([O:21][CH2:22][CH:23]4[CH2:27][CH2:26][NH:25][CH2:24]4)[N:20]=3)=[O:35])[N:11]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(OCC2CCNC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C

Procedure:
To a slurry of tert-butyl 3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate (1.291 g, 2.603 mmol) in CH2Cl2 (25 mL) was added TFA (5 mL) under N2. The reaction mixture was heated to reflux for 3 h, then cooled to rt. Saturated NaHCO3 solution (40 mL) was added and the precipitate was washed with EtOAc (3×40 mL) and H2O (2×10 mL), filtered and dried under high vacuum to give a white solid. MS m/z: 397.0 (M+H). Calc'd. for C19H21N6O2S-397.1.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22](Cl)[N:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:17][C:18]1[C:23]([C:24]#[N:25])=[C:22]([NH:16][CH:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][CH2:6]3)=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:21]=[CH:20][N:19]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (108 mg, 0.49 mmol), 4-amino-6-chloro-5-cyanopyrimidine (75 mg, 0.49 mmol) and DIPEA (171 μL, 0.98 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which point the solution became homogenous. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 434 as a pale yellow solid (125 mg, 75%). LCMS (Method K): RT 2.49 min [M+H]+ 340.1. 1H NMR (DMSO, 400 MHz): δ 8.02 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.27 (2H, br s), 7.09 (1H, dd, J=8.7, 3.3 Hz), 6.95 (1H, dd, J=12.3, 8.8 Hz), 5.60 (1H, dq, J=7.4, 6.8 Hz), 4.50-4.41 (2H, m), 4.36-4.27 (2H, m), 1.58 (3H, d, J=6.8 Hz)
Reaction SMILES: [F:1][C@:2]12[C@@H:24]([OH:25])[CH2:23][C@@:22]3([CH3:26])[C@@H:12]([CH2:13][C@@H:14]([OH:28])[C@:15]3([OH:27])[C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[C-]#N.[Na+].[CH:34](O)(C)[CH3:35]>>[F:1][C@:2]12[C@@H:24]([OH:25])[CH2:23][C@@:22]3([CH3:26])[C@@H:12]([CH2:13][C@@H:14]([OH:28])[C@:15]3([OH:27])[C:16](=[O:21])[C:17]([O:19][CH2:20][CH2:34][CH3:35])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1
Reactant: CC(C)O
Reactant: COC(=O)C(=O)[C@@]1(O)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: [C-]#N
Agent: [Na+]
Product: CCCOC(=O)C(=O)[C@@]1(O)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
A solution of (11β,16α)-9-fluoro-11,16,17-trihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid, methyl ester (1.0 g) in anhydrous isopropyl alcohol (100 ml) containing sodium cyanide (100 mg) is refluxed for 3.0 hours. The isopropanol is then removed by distillation in vacuo and the residue is washed with water, dried and crystallized to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH2:17][C:18]([O:20]CC)=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[C:8]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cnc(Nc2cccnc2CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ncccc1Nc1ncc(C)n(CC(=O)O)c1=O
Yield: 73.9 %

Procedure:
To a solution of 3-(2-Ethylpyrid-3-ylamino)-6-methyl-1-(ethoxycarbonylmethyl)pyrazinone (0.058 g, 0.183 mMol) from step 3 above in 6 mL of 1:1:1-tetrahydrofuran:methanol:water was added 183 μL (0.183 mMol) of 1N sodium hydroxide solution. The solution was stirred at ambient temperature for 18 h at which time 183 μL (0.183 mMol) of 1N hydrochloric acid solution was added. The solution was concentrated in vacuo several times from methanol and the residue was triturated with diethyl ether. The resulting precipitate was filtered off to afford the title compound as a beige powder (0.039 g; HPLC RT=3.13 min, method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH:36]=O)=[CH:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:36][C:31]4[NH:32][C:33]5[C:29]([CH:30]=4)=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:35][CH:34]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCCC4)ccc3[nH]2)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]S(C)(=O)=O)[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.4 %

Procedure:
A mixture of 1.16 g (0.006 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.93 g (0.006 mole) of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.65 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 21 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 40% ethyl acetate-hexane to give 2.45 g (70% yield) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:36]C)=[C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[NH:13][C:12](=[O:24])[C:11]=2[NH:25][CH2:26]N2C3C=CC=CC=3N=N2)[CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:36])=[C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[NH:13][C:12](=[O:24])[C:11]=2[NH:25][CH3:26])[CH:9]=1
Reactant: COc1ccc(Cl)cc1-c1c(NCn2nnc3ccccc32)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(-c2cc(Cl)ccc2O)c2cc(C(F)(F)F)ccc2[nH]c1=O
Yield: 27.1 %

Procedure:
Sodium borohydride(151.2 mg, 4.0 mmol) was added to a solution of 4-(5-chloro-2-methoxyphenyl)-3-[[(1H-benzotriazol-1-yl)methyl]amino]-6-(trifluoromethyl)quinolin-2(1H)-one (1.0 g, 2.0 mmol) in absolute ethanol and heated to reflux for thirty minutes. The reaction was cooled, acidified with 10% citric acid, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The resulting solid was then chromatographed on silica gel affording 4-(5-chloro-2-hydroxyphenyl)-3-(methylamino)-6-(trifluoromethyl)quinolin-2(1H)-one (200 mg, 26.1%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@@H:10]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:4].[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25]I.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25][N:15]1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:9][O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7]
Reactant: COC(=O)COCC#CCI
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Sodium hydride (60% dispersion in oil, 278 mg, 6.95 mmol) was added to a solution of (R)-6-(1-ethoxyethoxymethyl)piperidin-2-one (from example 1, step 1, 1.40 g, 6.96 mmol) in DMF (10 mL) at 0° C. After 1 h at 0° C., (4-iodo-but-2-ynyloxy)-acetic acid methyl ester (2.05 g, 7.65 mmol) in DMF (10 mL) was added via cannula and the reaction was allowed to warm to rt. After 15 min at rt, the reaction mixture solidified, so more DMF (3 mL) was added. After 18 h at rt, the reaction was treated with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×70 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→50% EtOAc/CH2Cl2, gradient) afforded 500 mg (21%) of {4-[(R)-2-(1-ethoxy -ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:6]([C:18]2[N:22]=[C:21]([N:23]3[CH2:26][CH:25]([OH:27])[CH2:24]3)[O:20][N:19]=2)[N:5]=1.CS(O[CH:33]([CH3:35])[CH3:34])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH:33]([O:27][CH:25]1[CH2:24][N:23]([C:21]2[O:20][N:19]=[C:18]([C:6]3[N:7]=[C:8]([N:10]([CH3:17])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:9]=[C:4]([NH2:3])[N:5]=3)[N:22]=2)[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)OS(C)(=O)=O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CC(O)C3)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC1CN(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)C1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) was added to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-azetidin-3-ol (Intermediate 166, 50 mg, 0.147 mol) in anhydrous DMF (0.5 mL) at 0 C under nitrogen and the mixture was stirred for 10 min. A solution of propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) in anhydrous DMF (0.5 mL) was then added and the mixture was stirred at room temperature for 18 h. Further sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) and propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) were then added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (10 mL) then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM) to afford the title compound as a light yellow glass (22 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH3:9][C:10]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([O-])(O)=O.[Na+]>>[C:10]([Si:13]([CH3:15])([CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 2-fluoro-5-hydroxypyridine (1.00 g, 8.84 mmol) and BDCS reagent (0.5 TBSCl, 1.0 imidazole in DMF) (35.4 mL, 17.7 mmol) was stirred at rt for 1 h. The reaction was poured into satd. aqueous NaHCO3 solution. The aqueous layer was extracted with ether. The combined extracts were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the title compound (1.96 g, 98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]([NH2:17])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1.N1C=CC=CC=1.Cl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH3:2][O:3][C:4](=[O:18])[C:5]([NH:17][C:26](=[O:28])[CH3:27])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: COC(=O)C(N)=Cc1c[nH]c2cc(Cl)ccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)NC(C)=O
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A 2-l. three-necked flask, equipped with a thermometer, a mechancal stirrer and a dropping funnel was charged with 101.2 g (ca. 0.35 moles) of crude pulverized alpha-amino-6-chloro-3-indoleacrylic acid methylester hydrochloride and 400 ml of acetic anhydride. The slurry was cooled to 15°. Then 32 g (0.40 moles) of pyridine was added with stirring over a 5 minute period, while the temperature was kept between 15° and 22°; after complete addition, virtually all starting hydrochloride went into solution. Stirring at 22° was continued for 20 minutes during which the product began to crystallize out. 200 ml of water was then added over 40 minutes, keeping the temperature at ca. 25°. Stirring at this temperature was continued for 11/2 hours. 900 ml of water was then added over 5 minutes and the slurry stirred at room temperature for an additional hour. The precipitate was collected by suction filtration, washed with 750 ml of water and dried at 60° (constant weight) to afford 92.9 g (90%) of product, as yellow crystals, m.p. 202-203°.