Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[C:11]=2[CH:22]=1)(=O)=O.[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32]([CH:36]=[CH2:37])=[N:33]2)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-].[Li+].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](/[CH:36]=[CH:37]/[C:7]3[CH:8]=[CH:9][C:10]4[CH:16]=[CH:15][C:14]5[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=5[C:12](=[O:21])[C:11]=4[CH:22]=3)=[N:33]2)=[CH:28][CH:27]=1
Reactant: O=c1c2ccccc2ccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: C=Cc1ccc2ccc(Cl)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c2ccccc2ccc2ccc(/C=C/c3ccc4ccc(Cl)cc4n3)cc12
Temperature: 120 °C
Reaction time: 10 h

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 0.89 g (2.5 mmol) of 3-trifluoromethanesulfonyloxy-5H-dibenzo[a,d]cyclohepten-5-one and 0.48 g (2.5 mmol) of 7-chloro-2-vinyl quinoline, and then, 100 mg (0.5 mmol) of palladium acetate, 420 mg (1.6 mmol) of triphenylphosphine and 2.1 g (24 mmol) of lithium bromide were added to the mixture and the atmosphere thereof was made nitrogen. Then, 5.0 ml (36 mmol) of triethylamine was added to the mixture, and the resulting mixture was stirred under nitrogen atmosphere at 120° C. for 10 hours.
Reaction SMILES: [CH:1]([Si:3]([Cl:6])([Cl:5])[Cl:4])=[CH2:2].[Cl:7][SiH:8]([Cl:10])[Cl:9]>>[Cl:4][Si:3]([Cl:6])([Cl:5])[CH2:1][CH2:2][Si:8]([Cl:10])([Cl:9])[Cl:7]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=C[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Yield: 98 %

Procedure:
As in Example 1, 53.3 grams (0.33 mol) of vinyltrichlorosilane was reacted with 46.1 grams (0.34 mol) of trichlorosilane to obtain 96.0 grams (yield 98%) of 1,2-bis(trichlorosilyl)ethane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[S:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[N:7]=2)=[CH:35]1
Reactant: OB(O)c1ccsc1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccsc2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 85 °C
Reaction time: 4 h

Procedure:
44 mg of 6-chloro-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one, 14 mg of thiophene-3-boronic acid and 36 mg of potassium carbonate are dissolved 1.5 ml of a 1:2 mixture of water and dimethoxyethane, and argon is passed through the solution for degassing. Addition of 7 mg of (1,1′-bis(diphenylphosphine) -ferrocene)palladium(II) chloride-dichloromethane complex is followed by stirring at 85° C. for 4 hours. For workup, it is diluted with water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by silica gel chromatography (n-heptane/ethyl acetate).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21](OC)=[O:22])([CH3:17])[CH3:16].[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH:15]([CH3:16])[CH3:17])=[O:3]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: COC(=O)c1ccccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2ccccc2OC(C)C)c1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A solution consisting of methyl 3-acetyl-4-hydroxy-benzoate (60 g) and methyl 2-isopropoxy-benzoate (120 g) in dioxane (400 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (45 g) in dioxane (200 ml). The mixture was kept for 4 hours at 80° C, cooled, then diluted with petroleum ether (600 ml), and subsequently filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallised from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-benzoyl)-methane (70 g); m.p. 105°-107° C) which was then refluxed for 15 minutes with formic acid 99% (280 ml). After cooling and dilution in water (one liter) and filtration, the collected precipitate was crystallised from acetone to obtain 6-carbomethoxy-2'-isopropoxy-flavone (60 g; m.p. 154°-155° C), which was hydrolysed with a solution of potassium hydroxide 1% (l. 1,020) in ethanol 95% at reflux temperature for 30 minutes. The mixture was cooled, acidified with acetic acid, concentrated under vacuum to obtain a precipitate, which was filtered, washed with ethanol (95%) and water to give, after crystallisation from ethanol, 6-carboxy-2'-isopropoxy-flavone (45 g; m.p. 209°-211° C).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:16]([Cl:17])=[C:15]([CH3:18])[NH:14][C:13]=1[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:32][C:31]([C:33](OC)=[O:34])=[N:30][N:29]=2)[CH2:24][CH2:23]1)=[O:20].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[C:16]([Cl:17])=[C:15]([CH3:18])[NH:14][C:13]=1[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:32][C:31]([CH2:33][OH:34])=[N:30][N:29]=2)[CH2:24][CH2:23]1)=[O:20]
Reactant: COC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnc(CO)o3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Diisobutylaluminum hydride (0.94 ml, 1 M solution in toluene, 0.94 mmol) was added dropwise to a solution of methyl 5-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3,4-oxadiazole-2-carboxylate (Example 302) (95 mg, 0.24 mmol) in THF (8 ml) at 0° C. The resultant mixture was allowed to slowly warm to room temperature and was stirred overnight. Potassium sodium tartrate (15 ml, 10% aqueous solution) and EtOAc (100 ml) were added to the reaction mixture and the resultant mixture was stirred vigorously for 1 h. The organic phase was separated, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by preparative reversed-phase HPLC (water/acetonitrile gradient, 10-95%) to yield 45 mg of the title compound.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[Nd].C([Al](C[CH:16]([CH3:18])[CH3:17])CC(C)C)C(C)C.[Cl-].[Cl-].C([Al+2])C>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH3:1][CH2:2][CH2:3][CH2:18][CH2:16][CH3:17]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: C=CC=C
Agent: CC[Al+2]
Agent: [Cl-]
Product: CCCCCC

Procedure:
Polymerization of 1,3-butadiene was conducted using a catalyst system comprising neodymium versatate (“NdV”), triisobutylaluminum (“TIBA”), and ethylaluminum dichloride (“EADC”) to prepare a control sample of cis-1,4-polybutadiene according to the following method. An oven-dried 800-mL glass bottle was capped with a self-sealing rubber liner and a perforated metal cap. After the bottle was thoroughly purged with a stream of dry nitrogen, the bottle was charged with 106 g of hexane and 227 g of a 1,3-butadiene/hexane blend containing 22.0 percent by weight of 1,3-butadiene to yield a 1,3-butadiene/hexane blend comprising 15 percent by weight 1,3-butadiene. The following catalyst ingredients were then charged into the bottle in the following order: (1) 3.00 ml of 0.68 M TIBA in hexane, (2) 0.90 ml of 0.0944 M NdV in cyclohexane, and (3) 0.80 ml of 0.159 M EADC in hexane. The bottle was tumbled for 50 minutes in a water bath maintained at 80° C. The polymerization was then terminated by addition of 3 ml of 12 percent by weight 2,6-di-tert-butyl-4-methylphenol solution in isopropanol. The resulting polymer cement was coagulated with 2 liters of isopropanol containing 0.5 g of 2,6-di-tert-butyl-4-methylphenol and then drum-dried. The yield of the polymer was 48.6 g. The Mooney viscosity (“ML1+4”) of the resulting polymer was determined to be 62.8 at 100° C. by using an Alpha Technologies Mooney viscometer with a large rotor, a one-minute warm-up time, and a four-minute running time. As determined by gel permeation chromatography (“GPC”), the polymer had a number average molecular weight (“Mn”) of 133,500, a weight average molecular weight (“Mw”) of 362,800, and a molecular weight distribution (“Mw/Mn”) of 2.72. The infrared spectroscopic analysis of the polymer indicated a cis-1,4-linkage content of 97.16 percent, a trans-1,4-linkage content of 2.01 percent, and a 1,2-linkage content of 0.83 percent. The properties of the polymer are summarized in Table 1.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>CCOCC>[C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:22])=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Yield: 57.7 %

Procedure:
A solution of 27 m moles (7.3 g) of the above 4-carbobenzoxyoxybenzoic acid and 27 m moles (5.6 g) of phosphorus pentachloride in 50 ml of ether was stirred for 24 hours at room temperature. After the reaction, deetherizing was carried out, and the obtained crystal was recrystallized from hexane, to obtain 4.5 g of 4-carbobenzoxyoxybenzoyl chloride [m.p. 65.5°-67.4° C⟧ (yield: 57%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[ClH:33].CCOCC>ClCCl>[ClH:33].[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 33 %

Procedure:
A mixture of tert-butyl 4-(3-(1-(3-bromophenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (0.45 g, 0.9 mmol), 2N HCl in ether (10 mL, 20.0 mmol) and dichloromethane (5 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in dichloromethane; this solution was washed with aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The yellow solid residue was dissolved in dichloromethane (0.5 mL) and reacted with 1N HCl in ether (1 mL). The resulting precipitates were collected by vacuum filtration, washed with ether and air dried to yield the title compounds as a yellow solid (0.13 g, 33%). 1H NMR (400 MHz, CDCl3): δ 8.71 (d, 1H), 8.05 (d, 1H), 7.50 (s, 1H), 7.39 (m, 1H), 7.23 (m, 2H), 6.19 (dd, 1H), 5.60 (d, 1H), 4.53 (m, 1H), 3.21 (m, 2H), 3.13 (m, 2H), 2.88 (m, 4H), 1.63 (d, 3H). MS (ESI) m/z: Calculated: 404; Observed: 405 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1ccc2c(c1)cc(B(O)O)n2C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3cc4cc(C)ccc4n3C)c(C)nc12
Yield: 9.7 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.29 mmol), 1,5-dimethyl-1H-indole-2-boronic acid (0.060 g, 0.32 mmol), 2M Na2CO3 (0.22 mL, 0.44 mmol), and n-PrOH (1.5 mL) is degassed with nitrogen for 10 minutes. Pd(OAc)2 (0.0013 g, 0.0058 mmol), and PPh3 (0.0046 g, 0.017 mmol) are added and the solution is heated at a reflux for two days. The solution is diluted with CH2Cl2 (50 mL), washed with 10% Na2CO3 (30 mL), water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The material is purified by ISCO (30%-50% EtOAc gradient) to furnish the title compound (0.010 g, 0.028 mmol, 10%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.95 (m, 4H), 2.48 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 3.32-3.41 (m, 1H), 3.58 (s, 3H), 6.59 (s, 1H), 6.70 (s, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.47 (s, 1H) ppm. LC/MS (m/z): calcd. for C23H28N4 (M+H)+: 361.6; found: 361.2.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)=[O:25])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(Oc2ccccc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
The 6-phenoxypyridine-3-amine (200 mg, 1.07 mmol) and indole-3-carboxylic acid (200 mg, 1.07 mmol) were dissolved in DMF (5 ml), DCC (200 mg, 1.07 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (60 mg, 17%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[C:31]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CCN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NCC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step 3 of Example 17 from tert-butyl (2R,4S)-2-(2-aminoethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (Step 2 of Example 19) and isobutyryl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C1COCC1.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=1)[CH:30]([C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=1)[OH:31])[CH3:2]
Reactant: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Oc1ccc(C(F)(F)F)cc1)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 48.3 %

Procedure:
A −78° C. solution of 2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (10.0 g, 38.1 mmol) in THF (80 mL) was transferred via cannula to a −78° C. solution of 1.5 M LDA-THF complex (45.8 mL, 68.7 mmol) in THF (80 mL). The resultant mixture was stirred for 5 minutes at −78° C. and then 3-benzyloxybenzaldehyde (7.3 g, 34.4 mmol) was added in one portion and the reaction mixture stirred at −78° C. for 5 minutes and was then was quenched with a −78° C. THF solution of acetic acid (6.82 g, 113.5 mmol). The reaction mixture was diluted with aqueous saturated NH4Cl and extracted with Et2O. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 19.84 g of crude product that was purified by flash chromatography using 8:1 then 4:1 hexanes:acetone to afford 7.88 g (44%) 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester as a mixture of diasteriomers. Rf=0.55 (1:1 hexanes:acetone). 1NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]#[N:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]4[NH:30][N:29]=[N:28][N:20]=4)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 125 °C

Procedure:
To a stirred solution of 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carbonitrile (0.036 g, 0.093 mmol) in DMF (1.0 mL) was added sodium azide (0.012 g, 0.18 mmol) and ammonium chloride (0.01 g, 0.18 mmol) and the mixture heated at 125° C. for 1.5 hours. The solvent was concentrated in vacuo and the residue co-evaporated with toluene. The crude product was dissolved in 10% MeOH in DCM and the insoluble material removed by filtration. The residue was triturated from MeCN, the solid collected and dried under vacuum. The solid was purified by reverse phase preparative HPLC to give the product as beige solid after lyophilisation (0.021 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:15][CH2:16][OH:17])=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:15][CH2:16][O:17][C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:26][CH:25]=3)=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1nc2c(Cl)nccn2c1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2c(Cl)nccn2c1CCOc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a suspension of methyl 8-chloro-3-(2-hydroxyethyl)imidazo[1,2-a]pyrazine-2-carboxylate (18 mg, 0.070 mmol) in toluene (1 mL) was added 4-trifluoromethoxyphenol (0.014 mL, 0.106 mmol), Ph3P (27.7 mg, 0.106 mmol), and DIAD (0.021 mL, 0.106 mmol). After 30 min, the reaction was concentrated in vacuo and then purified on silica (gradient elution, 0-100% EtOAc/hexanes) to yield the title product (10 mg). HRMS (ESI) calc (M+H)+=416.0619. found 416.0616.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:32][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.83 h
Yield: 83 %

Procedure:
N-t-butoxycarbonylvaline (2.2 g, 10 mmol) is dissolved in, dry THF under nitrogen, and to this is added 2.0 g (12 mmol) of carbonyldiimidazole. After this mixture is stirred for 50 min, 2.0 mL (20 mmol) of isobutylamine is added. After 1 week, the mixture is concentrated, dissolved in ethyl acetate, and washed successively with aqueous potassium hydrogen sulfate, water, and brine. It is dried over anhydrous sodium sulfate and concentrated to 2.27 g (8.3 mmol, 83%) of the title compound as a white solid. NMR (CDCl3) δ 6.0 (br, 1H), 5.07 (br d, 1H), 3.83 (m, 1H), 3.10 (m, 2H), 2.14 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H), 1.01-0.90 (overlapping d, 12H). HRMS (ESI) calcd for C14H28N2O3+H1 273.2178, found 273.2180
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11](=[O:14])[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:15][C:16](=O)[C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])[CH2:3][CH2:2]1>CC(O)=O>[NH2:19][C@H:17]([C:16]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[C:10]([C:11]([NH:12][CH3:13])=[O:14])=[CH:9][CH:8]=[CH:7][C:6]=2[N:15]=1)[CH3:18]
Reactant: CNC(=O)c1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1NC1CC1
Solvent: CC(=O)O
Product: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of (S)-tert-butyl 1-(2-(cyclopropylamino)-3-(methylcarbamoyl)phenylamino)-1-oxopropan-2-ylcarbamate (1.1 g, 2.9 mmol) in AcOH (30 mL) was heated at 65° C. for 2 h, and cooled to rt. After concentrating under reduced pressure, the residue was subjected to 4 M HCl in 1,4-dioxane (20 mL) and stirred at rt for 40 min. The mixture was concentrated under reduced pressure and dissolved in water (5 mL) basified with 1 N NaOH to pH 9.5. The mixture was concentrated and triturated with MeOH-CDM (1:1). The crude product was purified by column chromatography on a silica gel column using DCM-MeOH—NH4OH (9:1:0.05) as eluent to give (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.23 (dd, J=8, 8 Hz, 1H), 6.09 (br, 1H), 4.61 (t, J=8 Hz, 1H), 3.53-3.46 (m, 1H), 3.11 (d, J=4 Hz, 3H), 1.63 (d, J=8 Hz, 3H), 1.22-1.07 (m, 2H), 1.02-0.94 (m, 1H), 0.90-0.83 (m, 1H); LC-MS (ESI) m/z 259.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO>[Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(C)c(-c2nc(C)[nH]c2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2cc(C(=O)O)ccc2C)c(Cl)[nH]1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoate (compound 7.2, 10 mg, 0.038 mmol) in methanol (2 mL) and aqueous NaOH (2M, 0.2 mL, 0.4 mmol) was stirred at 50° C. for 16 hrs. The organic solvent was removed under reduced pressure and aqueous HCl (2 M) was added to the residue until a pH˜3-4 was attained. The solvents were removed under reduced pressure to produce a white solid which was a mixture of the title compound and salts and used in the next step without further purification. m/z (ES−) 249 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[NH:8][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:7]1[C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[N:8]=1
Reactant: Cc1nc2c(O)cccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2cccc(O)c2n1

Procedure:
8-Hydroxy-2-methyl-4(3H)-quinazolinone (0.01 mol) and phosphorus oxychloride (10 mL) were heated under reflux for 30 min. The excess phosphorus oxychloride was removed under reduce pressure and the residue was added to a mixture of ice (50 g) and water (50 ml), and the pH adjusted to 6 (aqueous ammonia). 4-Chloro-8-hydroxy-2-methyl-quinazoline (A2) was isolated via filtration.