Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2=[O:16].[Br-].[Na+].CC1(C)CCCC(C)(C)[NH+]1[O-].Cl[O-].[Na+].C(=O)([O-])O.[Na+]>COCCOC.O.C(OCC)(=O)C>[CH3:18][O:17][C:5]1[C:4]([CH2:3][CH:2]=[O:1])=[C:13]2[C:8]([C:9](=[O:16])[CH2:10][C:11]([CH3:14])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1CCO)OC(C)(C)CC2=O
Agent: CC1(C)CCCC(C)(C)[NH+]1[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
248.3 g (content 232.7 g, 0.930 mol) of 8-(2-hydroxyethyl)-7-methoxy-2,2-dimethylchroman-4-one, 294.0 g (content 274.9 g, 1.098 mol) of the same compound and 7614 mL of ethyl acetate were put in a 15 L four-necked round bottom flask and stirred. Cooling of this suspension was started in a cold bath set to −4° C., and 161.9 g (1.574 mol) of sodium bromide, 508 mL of water, 3.17 g (20.28 mmol) of 2,2,6,6-tetramethylpiperidine oxide were put therein sequentially. After the inner temperature reached 0° C., a mixture of 5.536 mol of sodium hypochlorite solution and 2538 g of 7% (W/W) sodium hydrogen carbonate aqueous solution were added dropwise into the flask over about 2 hours. After the dropwise addition was completed, the temperature of the cooling bus was changed to 0° C. and stirring was continued for 45 minutes. The reaction mixture was transferred to a 20 L separatory funnel and the aqueous layer was discarded. The organic layer was washed with 2030 g of 10% sodium chloride aqueous solution and 2030 mL of water sequentially. The obtained organic layer was concentrated in vacuo (40° C.) and 743.7 g of slurry was obtained. 500 mL of DME was added to the obtained slurry to form a solution and concentrated in vacuo (40° C.) again and 500 mL of DME was added again to the precipitates so that they were dissolved. This solution was transferred to a 5 L four-necked round bottom flask and warmed in a 40° C. water bath. 515 mL of DME was further added and stirred at 183 rpm and about 500 mL of water was cast therein and cooling with an ice-water bath was started 4 minutes later. Seed crystals were added and the mixture was stirred for about 1 hour and 515 mL of water was further added over about 30 minutes. After stirring for about 1.3 hours, 1523 mL of heptane was further added over 1 hour and stirred at the same temperature for about 1 hour or more. Precipitated crystals were collected by filtration, washed with a mixture of DME/water/heptane [about 600 mL, DME/water/heptane=1/1/1.5]. The crystals were dried in vacuo (bath temperature: 40° C.) till the weight became almost constant and the title compound was obtained as a yellowish white solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([Br:7])=[N:4][C:3]=1[Br:8].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.[NH4+].[Cl-]>C1COCC1>[Br:7][C:5]1[N:4]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:3]([Br:8])=[C:2]([Br:1])[N:6]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reaction time: 0.33 h

Procedure:
3.04 g of tribromoimidazole is dissolved in 20 cm3 of anhydrous THF. 550 mg of NaH at 50% in oil is added in small portions. After 20 minutes at ambient temperature, 1.95 ml of 2-(trimethylsilyl) ethoxy methyl chloride is added. After 30 minutes at ambient temperature, the reaction medium is hydrolyzed with a saturated solution of NH4Cl, followed by extraction with AcOEt, drying and evaporating to dryness. Chromatography is carried out on silica eluting with cyclohexane/AcOEt (9-1) and 4.2 g of expected product (oil) is recovered.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].[Br:29][C:30]1[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=[C:32]([Br:38])[C:31]=1[CH2:39][NH2:40].CCN(CC)CC>CCO>[Br:29][C:30]1[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=[C:32]([Br:38])[C:31]=1[CH2:39][NH:40][C:21]([C:19]1[N:20]=[C:9]2[C:8]3([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]3)[CH2:11][N:10]2[C:17](=[O:26])[C:18]=1[OH:25])=[O:23]
Reactant: Cc1c(F)cc(Br)c(CN)c1Br
Reactant: COC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N(C)C(=O)C(=O)N(C)C)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(Br)c(CNC(=O)c2nc3n(c(=O)c2O)CC2CCC3(N(C)C(=O)C(=O)N(C)C)CC2)c1Br
Yield: 56.1 %

Procedure:
A solution of methyl 10-(((dimethylamino)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.10 g, 0.246 mmol), (2,6-dibromo-4-fluoro-3-methylphenyl)methanamine (0.225 g, 0.758 mmol) and Et3N (0.279 mL, 2 mmol) in EtOH (5 mL) was heated at reflux for 48 h. Then, cooled and purified by preparative HPLC to afford the title compound (0.0906 g, 0.138 mmol, 56% yield) as a white solid after crystallization from methanol/H2O. 1H NMR (500 MHz, CDCl3) δ: 12.18 (1 H, s), 9.08 (1 H, s), 7.32 (1 H, d, J=8.5 Hz), 4.96 (2 H, d, J=8.2 Hz), 4.78-4.90 (1 H, m), 3.57-3.72 (1 H, m), 3.36-3.49 (1 H, m), 2.94 (3 H, s), 2.93 (3 H, s), 2.76 (3 H, s), 2.48-2.54 (1 H, m), 2.34 (3 H, d, J=2.1 Hz), 2.00-2.10 (4 H, m), 1.71-1.87 (2 H, m), 1.45-1.53 (1 H, m). LCMS (M+H) calcd for C25H29Br2FN5O5: 656.05; found: 656.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][C:3]=1[CH3:15].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=2)[O:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2nc(CO)co2)ccc1Cl
Solvent: ClCCl
Product: Cc1cc(-c2nc(CCl)co2)ccc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
136 mg (0.61 mmol) of the compound from Example 27A are suspended in 2 ml of dichloromethane. The suspension is cooled to 0° C., and 49 μl (0.67 mmol) of thionyl chloride are added slowly. The reaction solution is stirred at RT overnight. The solvent is then removed on a rotary evaporator. The residue is used without further purification in the subsequent reactions.
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:22][C:21]3[S:23][CH:24]=[CH:25][C:20]=3[C:19]([C:26](O)=[O:27])=[CH:18][C:17]=2[CH:29]=1.O1CCCC1>O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:22][C:21]3[S:23][CH:24]=[CH:25][C:20]=3[C:19]([CH2:26][OH:27])=[CH:18][C:17]=2[CH:29]=1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2Sc2sccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCC1=Cc2cc(Cl)ccc2Sc2sccc21

Procedure:
To 40 ml of abs. ether is added at 3° under nitrogen 0.76 g (0.02 mole) of lithium aluminium hydride, and there is then added dropwise at 5° with stirring, in the course of half an hour, a solution of 2.9 g (0.01 mole) of 7-chlorobenzo[f]thieno [2,3-b]thiepin-4-carboxylic acid in 60 ml of abs. ether and 20 ml of abs. tetrahydrofuran. The mixture is subsequently stirred for 2 hours at room temperature; 4 ml of water is then slowly added dropwise at 5°, and the precipitate is filtered off with suction. The filtrate is concentrated in vacuo; the crude residue is chromatographed on a silica-gel column, and by elution with chloroform is yielded 7-chlorobenzo[f]thieno [2,3-b]thiepin-4-methanol, m.p. 117°-120°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl.Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
A solution of methanesulphonyl chloride (6.3 g) in dichloromethane was added to a stirred, cooled (0°-5° C.) solution of methyl 2-amino-4-chlorobenzoate (9.5 g) in dichloromethane. Triethylamine (7.1 g) was then added and the mixture was stirred at 0°-5° C. for 10 minutes and then at room temperature for 0.5 hours. The mixture was diluted with 2N hydrochloric acid. The organic phase was separated, washed with water, dried and evaporated. The crude product was purified by column chromatography to yield methyl 4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid, (3.6 g) m.p. 125.5°-128.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:9])[CH2:15][CH2:14]1)[CH3:35]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 94.3 %

Procedure:
This compound was prepared according to the procedure used in Example 7. A mixture of 4.6 g (0.015 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.8 g (0.015 mole) of ethyl 8-bromooctanoate, 6.4 g (0.061 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 50 ml of N,N-dimethylformamide gave 6.7 g of a dark oil. The oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPAK® 500/silica; ethyl acetate-hexane 2:1; flow rate 150 ml/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 4.3 g (72%) of the title compound as a viscous, yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)[CH:7]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C(=O)Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)ccn2)CC1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-methylpiperazine to give the title compound in 69% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.4 (m, 4H), 3.53 (m, 8H), 3.71 (m, 4H), 7.09 (m, 2H), 7.25 (d, 2H), 7.53 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 1H), 10.19 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 536.
Reaction SMILES: [CH:1]([C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:43])[CH2:40][C:41]#[N:42])[CH2:35][CH2:34]1.N1CCCCC1>C(Cl)Cl>[C:41]([C:40]([C:39]([N:36]1[CH2:35][CH2:34][O:33][CH2:38][CH2:37]1)=[O:43])=[CH:1][C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:42]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCC(=O)N1CCOCC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 20 ml vial 2-(4-formylanilino)-N-isopropyl-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 0.11 mmol), 3-morpholino-3-oxopropanenitrile (33.99 mg, 0.22 mmol) and piperdine (0.02 ml, 0.22 mmol) were mixed and stirred overnight. The residues was dissolved in minimum CH2Cl2, loaded on silica gel column, and eluted with EtOAc:hexane, 0, 50, 80, 100% to get 60 mg of 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=C)[CH2:9][CH2:8][N:7]1[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:5])[CH3:2].CC[OH:25]>Cl.[Zn]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=[O:25])[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:16])/[C:17](/[CH3:22])=[CH:18]/[CH:19]=[CH:20]\[CH3:21])=[O:5])[CH3:2]
Reactant: CCO
Reactant: C=CCC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(=O)OCC
Agent: Cl
Agent: [Zn]
Product: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
(2S,3R)-3-But-3-enyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid ethyl ester(1.0 g, 3.32 mmol) is dissolved in EtOH(10 mL) with HCl(0.5 mL, 37%), and cooled to −70° C. Ozone gas is bubbled though the solution for about 10 min or until the solution is turned very light blue color. The nitrogen gas is bubbled though the solution for 15 min to remove excess ozone in the solution. To the cool solution is added Zn dust(0.43 g. 6.6 mmol) and HCl(0.5 mL, 37%), and stirred at r.t. for 20 min. After filtration the solution is diluted with 50 mL of CH2Cl2 and washed with saturated NaHCO3(10 mL) and 2×20 ml of water. After dried and concentrated, a colorless liquid(1.0 g) is obtained without further purification for next step reaction. (NMR and MS data confirmed, U-4117-51-30).
Reaction SMILES: Br[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19].C(N(CC)CC)C.O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][S:20]([CH:18]=[CH:19][C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)(=[O:22])=[O:21]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reactant: C=CS(C)(=O)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C=CS(C)(=O)=O)c(C=O)cc21
Yield: 61.6 %

Procedure:
A solution of 0.537 g (1.82 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.579 g (5.46 mmol) of methyl vinyl sulfone, 0.191 g (0.27 mmol) of tetrakis(triphenylphosphine) palladium and 5.23 g (51.7 mmol) of triethylamine in 12 ml dimethylformamide was heated to 100° C. under argon for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (elution with 25% ethyl acetate/hexane) to afford 0.359 g (62%) of 3-(2-methylsulfonylvinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (M+1=321).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:20]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-phenyl-1,2-ethanediol (1.38 g, 10 mmole), immidazole (817 mg, 12 mmole), and tert-butylchlorodimethylsilane (1.81 g, 12 mmole) in DMF 15 (ml) was stirred at 0° C. for 1.5 hrs and then at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:4) as eluent. 2-(tert-butyidimethylsilyl)oxy-1-phenylethanol was obtained as an oil (2.6 g, 100% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([N:34]=[C:35]=[O:36])=[C:27]([CH:33]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:35]([NH:34][C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:33][C:27]=1[C:28](=[O:29])[N:30]([CH3:31])[CH3:32])=[O:36])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc(Br)ccc1N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)NCCN(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a solution of (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (100 mg, 0.574 mmol) in DMF (2 mL) was added diisopropylethylamine (0.3 mL, 1.75 mmol) and 5-bromo-2-isocyanato-N,N-dimethyl-benzamide (154 mg, 0.572 mmol). The solution was stirred for 18 hours at 80° C. Ethyl acetate was added to the reaction mixture, and the combined mixture was washed 3 times with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was recrystallized from a mixture of ethyl acetate and dichloromethane to give 75 mg (30%) of {2-[3-(4-bromo-2-dimethylcarbamoyl-phenyl)-ureido]-ethyl}-methyl-carbamic acid tert-butyl ester. 1H-NMR (250 MHz, CDCl3) δ 11.0 (br s, 1H), 8.35 (d, J=9.1 mmol), 7.77 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=9.0 Hz, 1H), 3.45-3.55 (m, 5H), 2.97 (s, 6H), 2.86 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:17][C:15]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.CN.CO>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:17][CH3:15])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(F)cn1
Reaction time: 15 h
Yield: 91 %

Procedure:
5-Fluoropyridine-2-carboxylic acid (495 mg, 3.51 mmol) was dissolved in methylene chloride (10 mL), and HOBt.H2O (591 mg, 3.86 mmol), WSCI.HCl (1.35 g, 7.02 mmol), triethylamine (2.44 mL, 17.5 mmol) and 40% methylamine/methanol solution (0.82 mL, 10.5 mmol) were added, followed by stirring for 15 hours. To the reaction solution, water (30 mL) was added, and extraction was carried out twice with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (490 mg, yield 91%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH2:25]C1C=CC(C2OC3C=CC=CC=3N=2)=CC=1OC.N1CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:25]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCC1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCCC1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]-1,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 0.942 mmol) was reacted with piperidine (279 μL, 2.83 mmol) and triethylamine (394 μL, 2.83 mmol) in CH2Cl2 (5 mL) to afford the desired 2-[3-methoxy-4-(piperidin-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3-d, 300 MHz) δ 7.86–7.83 (m, 1H), 7.79–7.76 (m, 1H), 7.73 (s, 1H), 7.61–7.55 (m, 2H), 7.37–7.34 (m, 2H), 3.96 (s, 3H), 3.59 (s, 2H), 2.47 (br, 4H), 1.66–1.58 (m, 4H), 1.46–1.45 (m, 2H). MS (ESI) 323 (M+)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:25]2[CH2:26][CH2:27][C:22]([OH:21])([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH2:23][CH2:24]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 18.7 %

Procedure:
A mixture of 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (2.0 g, 6.9 mmol), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (1.06 g, 5.18 mmol), potassium carbonate (1.43 g, 10.35 mmol) and 2-butanone (40 ml) was stirred for 15 h at 60° C. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-benzamide (445 mg, 19%) as a light yellow solid. MS: me/e =459 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[OH:28].C(N(CC)C(C)C)(C)C>C(O)(C)C.O>[OH:28][CH:16]1[CH:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(O)C1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.61 g, 2.8 mmol) (Example 1, Step 2), tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (from Aurora, 0.95 g, 4.4 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.7 mmol) in isopropyl alcohol (7.4 mL) was heated at 90° C. for 2 h. The resulting mixture was diluted with water. The precipitate was collected by filtration, washed with water and air-dried to give the desired product (1 g, 89%). LCMS calculated for C17H23N4O5S (M+H)+: m/z=395.1. Found: 395.0.