Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:7]1[S:6][C:5]([CH:9]=[O:10])=[C:4]([CH3:3])[CH:8]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Br)sc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Following the preparation as described in U.S. Publication No. 2006/0199836, Br2 (3.67 mL, 71.3 mmol) was added to a solution of 3-methylthiophene-2-carbaldehyde (8.55 mL, 71.3 mmol) in chloroform (59.4 mL) dropwise at 0° C. over a period of 20 min. The reaction was allowed to slowly warm to room temperature and stir for 2 h. The brown/red solution was diluted with 150 mL of CH2Cl2 and washed with water, 1.5 M K2HPO4 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 50:50) to afford 13.9 g (72% yield) of the title compound as a brown solid: 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 6.97 (s, 1H), 2.54 (s, 3H); HPLC retention time: 2.718 min., LCMS (ES): m/z 207 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[C:20]=1[CH3:27])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([O:15][C:16](=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[C:20]=1[CH3:27])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1c(CO)cccc1OCC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C=O)cccc1OCC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.46 mL, 5.25 mmol) was added dropwise to a solution of dimethyl sulfoxide (0.88 mL, 12.50 mmol) dissolved in dichloromethane (40 mL). The mixture was cooled to −78° C. and allowed to stir for 1 hour. A solution of (3-hydroxymethyl-2-methylphenoxy)acetic acid tert-butyl ester (1.26, 5.00 mmol) in dichloromethane was cannulated into the reaction mixture and allowed to stir at −78° C. for an additional hour. Triethylamine (3.49 mL, 25 mmol) was added. The reaction mixture was allowed to warm to room temperature, poured into water, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 2N hydrochloric acid and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography, eluting with hexane/acetone, gave (3-formyl-2-methylphenoxy)acetic acid tert-butyl ester as a slightly yellow crystalline solid (1.07 g, 85.9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=3[CH:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Reactant: BrCC1CCCCC1
Product: CC1(C)OC(=O)c2cc(OCC3CCCCC3)ccc2O1

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38.a) and (bromomethyl)cyclohexane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 291.05 (M+1)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][CH3:29])=[O:27].C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])[C:26](=[O:27])[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccc1CCNCc1ccccc1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N(CCc1ccccc1Br)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.48 g of N-benzyl-2-(2-bromophenyl)ethanamine in solution in 50 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 0° C. 1.2 cm3 of triethylamine are added to the reaction mixture, then 0.67 cm3 of methyl chloroformate is introduced using a syringe. The reaction mixture is kept stirring for 1 h at 0° C., then 5 h at a temperature close to 20° C. The reaction mixture is poured into a mixture containing ice, ethyl acetate and water. Stirring is continued for 10 min. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, then concentrated using a rotary evaporator under reduced pressure (5 kPa). The brown oil obtained is purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 70% cyclohexane/30% ethyl acetate). After concentrating the fractions under reduced pressure, 2.51 g of methyl benzyl[2-(2-bromophenyl)ethyl]carbamate are obtained in the form of an oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCN(C)CC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added N-methyl piperazine (9.3 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 91% conversion to product. A further portion of N-methyl piperazine (9.0 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated 98% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (Example 9) as a light orange solid (26 mg, 47%): m/z 661 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69-2.60 (3H, bm), 2.88-2.73 (3H, bm), 3.17-2.95 (4H, bm), 5.39 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.66-7.56 (3H, m), 7.98 (1H, d), 8.37-8.28 (3H, m), 8.73 (1H, s), 8.91 (1H, s), 10.12 (1H, s).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)[N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CN=3)N(C3C(=O)N(C)C=C(Cl)C=3)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:21][C:16]1[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:34]4[C:35]([O:37][CH3:38])=[N:36][C:31]([O:30][CH3:29])=[N:32][CH:33]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1ccc(F)c(Cl)c1)C2=O
Agent: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1cc(Cl)cn(C)c1=O)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cn2)N(c2ccc(F)c(Cl)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(3-chloro-4-fluoro-phenyl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BL) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. ESI-MS: tR=1.23 min, [M+H]+ 542/544 (LC-MS 1).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[H-].[Li+].[CH2:9]([OH:12])[CH2:10][OH:11]>[Cu].S([O-])([O-])(=O)=O.[Cu+2]>[S:4]1[CH:5]=[CH:6][C:2]([O:11][CH2:10][CH2:9][OH:12])=[CH:3]1
Reactant: OCCO
Reactant: Ic1ccsc1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Product: OCCOc1ccsc1
Temperature: 100 °C

Procedure:
To a solution of 1.0 g (4.76 mmol) 3-iodothiophene in 5 ml ethylene glycol is added 109 mg (1.71 mmol) copper powder, 114 mg (0.714 mmol) copper(II)sulphate and 151 mg (19.0 mmol) lithium hydride. The reaction mixture is heated overnight in a sealed flask at 100° C. The reaction mixture is filtered through Celite and evaporated. The resulting oil is then filtered through a 50 g silica pad and eluted with ethyl acetate/hexanes (7:3) to give after evaporation 750 mg of an orange liquid, which is used without purification directly in the next reaction.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:22]=[O:23].P(Cl)(Cl)(Cl)=O>O>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:22]=[O:23])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 95 °C

Procedure:
101.4 g of triphenylamine and 35.5 mL of dimethyl formamide (DMF) were placed in a three-neck flask, and while stirring and cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. The temperature was raised to 95° C. The mixture was reacted for 5 hours. The reaction solution was poured into 4 L of warm water and stirred for one hour. The precipitate was collected and washed in a 1:1 mixture solution of ethanol/water. 4-(N,N-diphenylamino)benzaldehyde was obtained. The yield was 91.5 g (yield rate of 81.0%). The melting point was 128.6°-130.1° C.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:11])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].CN(C=O)C.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:11]/[C:4](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3]/[CH2:2][O:1][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC/C=C(/C)CCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Nerol (150 g, 972 mmol) was added dropwise to a DMF (1.501) suspension of sodium hydride (60%, 38.9 g, 973 mmol) under nitrogen gas stream at room temperature. The reaction solution was stirred at room temperature for one hour and then cooled to 0° C. After tetra-n-butyl ammonium iodide (35.9 g, 97.2 mmol) was added to the reaction solution, 4-methoxybenzyl chloride (148 g, 926 mmol) was added dropwise. The reaction solution was stirred at 0° C. for one hour and then at room temperature for six hours. Water was added to the reaction solution, which was then extracted with n-heptane. After the obtained organic layer was washed with water and brine (saturated solution of sodium chloride) sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=1:0→30:1→25:1) to obtain the title compound (246.7 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[C:7]([OH:16])[N:6]=1.[C:21](Cl)(=[O:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:11]([C:9]1[N:10]=[C:5]([CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[Br:1])[NH:6][C:7](=[O:16])[C:8]=1[O:15][C:21](=[O:23])[CH3:22])=[O:12]
Reactant: COC(=O)c1nc(Cc2ccccc2Br)nc(O)c1O
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1OC(C)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
In a round-bottomed flask, methyl 2-(2-bromobenzyl)-5,6-dihydroxypyrimidine-4-carboxylate (300 mg, 885 μmol) was combined with DCM (10 ml) to give a brown suspension. Acetyl chloride (1M in DCM) (2.21 ml, 2.21 mmol) was added slowly at room temperature. The mixture was stirred for one hour and then poured onto aqueous saturated NH4Cl solution and extracted with DCM. The organic phase was washed with brine solution, dried (Na2SO4), and evaporated to dryness under reduced pressure. Chromatography (SiO2; DCM) provided the title product as a white solid (0.33 g; 97%). LCMS: m/z=381/383 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][C:17]([CH3:28])([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH3:18])[C:12](O)=[O:13])[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:35][C@H:36]1[C@@H:39]([C:40]([O:42][CH3:43])=[O:41])[NH:38][C:37]1=[O:44].C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCCC1.O.C(N(CC)CC)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][C:17]([CH3:28])([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[O:20])[CH3:18])[C:12]([NH:35][C@H:36]2[C@@H:39]([C:40]([O:42][CH3:43])=[O:41])[NH:38][C:37]2=[O:44])=[O:13])[N:10]=1)=[O:4]
Reactant: CC(C)(ON=C(C(=O)O)c1csc(NC(=O)CCl)n1)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)C(=NOC(C)(C)C(=O)OCC[Si](C)(C)C)c1csc(NC(=O)CCl)n1
Reaction time: 2 h

Procedure:
In 25 ml of methylene chloride is dissolved 820 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetic acid, and under ice-cooling 221 mg of triethylamine and then 380 mg of phosphorus pentachloride are added. The mixture is stirred under ice-cooling for 15 minutes and then at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 5 ml of tetrahydrofuran to prepare a solution containing the acid chloride. On the other hand, 219 mg of cis-3-amino-4-methoxycarbonyl-2-oxoazetidine is dissolved in a mixture of 5 ml of tetrahydrofuran and 10 ml of water, followed by addition of 638 mg of sodium hydrogen carbonate under ice-cooling. To this solution is added dropwise the above acid chloride solution under stirring. The mixture is stirred under ice-cooling for 15 minutes and then at room temperature for one hour and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is distilled off to give cis-3-{2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetamido}-4- methoxycarbonyl-2-oxoazetidine (syn-isomer).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.C(OCC)(=O)C>C1COCC1.O>[Si:9]([O:7][CH2:6][CH2:5][C:2]([CH3:8])([CH3:1])[CH2:3][OH:4])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(CO)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)CCO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A solution of 2,2-dimethyl-1,4-butanediol (8.01 g, 67.8 mmol) in dry THF (80 mL) was treated with t-butyldimethylsilyl chloride (10.2 g, 67.8 mmol) and imidazole (4.60 g, 67.6 mmol). After 24 h at room temperature, work-up with ethyl acetate and water followed by drying the organics and concentration gave a crude product, which was purified by silica gel flash chromatography (being eluted with 5% ethyl acetate in hexane) to afford 11.0 g (Y: 70%) of 4-t-butyldimethylsilyloxy-2,2-dimethyl-1-butanol (XXVIIb) as a colorless oil; 1H-NMR (DMSO-d6) δ ppm: 4.43 (t, 1H) 3.61 (t, 2H) 3.05 (d, J=2.7 Hz, 2H) 1.38 (t, 2H) 0.83 (s, 9H) 0.78 (s, 6H) 0.00(s, 6H); HRMS Calcd for C12H29O2Si (MH+): 233.1937, found: 233.1930.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[H-].[Na+].O>C1(C)C(C)=CC=CC=1>[CH:5]([C:4]1([CH3:8])[NH:9][C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:2][C:1]1=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)C1(C)NC(c2ccc3ccccc3n2)=NC1=O
Yield: 78.3 %

Procedure:
To a slurry of N-(1-carbamoyl-1,2-dimethylpropyl)-2-quinolinecarboxamide (16.04 g, 0.0562 mol) in xylene (610 ml) under nitrogen is added a 50% oil dispersion of sodium hydride (2.7 g, 0.056 mol) at 20° C. The reaction is heated to reflux for 2 hours, cooled and water (50 ml) added. The aqueous layer is extracted with methylene chloride and the organic layers combined and evaporated to give a yellow oil, 17 g. Purification is accomplished by passing through a silica gel column using hexane-ethyl acetate as solvent. A pale yellow solid is obtained and is recrystalized from ethyl acetate to give 11.77 g (78%) of white product, mp 112°-117° C. Anal. calcd. for C16H17N3O: C, 71.88; H, 6.41; N, 15.72. Found: C, 71.91; H, 6.47; N, 15.70.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2OCCO2)=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl:30]([O-:34])(=[O:33])(=[O:32])=[O:31].[Li+]>>[Cl:30]([O-:34])(=[O:33])(=[O:32])=[O:31].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:20]([CH:21]=1)=[CH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=1[CH:8]=2
Reactant: COc1ccc(C[n+]2ccccc2C2OCCO2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc2c[n+]3ccccc3cc2c1

Procedure:
A mixture of 1-(4-methoxybenzyl)-2-(1,3-dioxolan-2-yl)pyridinium chloride (15 g, 0.049 mol) in 300 g of polyphosphoric acid was allowed to react at 120° C. for 3 hours. The reaction mixture was poured onto ice with stirring. The mixture was neutralized with dibasic sodium phosphate and an aqueous solution of lithium perchlorate (1.1 equiv.) was added. The precipitated solid was filtered and dried to yield 9-methoxybenzo[b]quinolizinium perchlorate (Formula II: R2 =OCH3 ; R1 =H; X- =ClO4-), as a yellow solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:33])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl>C(O)(C)C>[ClH:1].[C:26]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=3)=[O:33])[CH2:18][CH2:17]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1

Procedure:
A mixture of 17.7 g (0.038 mole) of 4'-fluoro-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride, 200 ml of 37% HCl, and 200 ml of isopropyl alcohol was heated on a steam bath for 4 hours. The solvent and excess acid were removed at reduced pressure. The remaining residue was treated with benzene and ethanol and heated to remove excess acid. The excess benzene and ethanol were removed, and the residue was dissolved in hot butanone to which ether was added. Upon cooling a solid formed which was recrystallized from ethyl acetate to give the desired product M.P. 190°-191° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:20])[C:18]#[CH:19])[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1>C(N(CC)C1C=CC=CC=1)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:19]=[CH:18][CH:17]([CH3:20])[O:16][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1
Reactant: C#CC(C)Oc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)C=C2
Yield: 36.5 %

Procedure:
A solution of 2,4-diamino-5-[3,4-dimethoxy-5-(1-methyl-2-propynyloxy)benzyl]pyrimidine (4.28 g, 13.0 mmol) in N,N-diethylaniline (200 mL) was refluxed under nitrogen for 0.5 hr. The hot solution was filtered to remove dark tarry material. The filtrate was cooled and diluted with hexanes (200 mL). The precipitate (3.8 g) was recrystallized from ethanol to give title compound as off-white powder (1.56 g, 37%); mp 219°-221° dec. Anal. Calcd for C17H20N4O3 : C, 62.18; H, 6.14; N, 17.06. Found: C, 61.91; H, 6.20; N, 16.93.
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[ClH:1].[NH:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1
Reactant: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1CNC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
4N hydrochloric acid in ethyl acetate (12.7 ml) and 20% palladium hydroxide (3.57 g) were added to a solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) in methanol (360 ml), followed by stirring under a pressurized hydrogen atmosphere (0.4 MPa) at room temperature for 11 hours. The catalyst was removed by filtration, and washed with methanol and water. The filtrate was concentrated to give a crude product of the target compound as a pale yellow oil, which was used in the next reaction supposing that the reaction proceeded quantitatively and 1.93 g of the product was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[N:9][C:5]=2[CH:4]=1.C1COCC1.O.[OH-].[Li+:31]>C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O-:13])=[O:12])=[N:9][C:5]=2[CH:4]=1.[Li+:31]
Reactant: CCOC(=O)Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Reaction time: 8 h
Yield: 114.7 %

Procedure:
A solution of ethyl 2-(5,7-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)acetate (250 mg, 0.74 mmol) in 4:1 THF/water (4 mL) was treated with lithium hydroxide (21 mg, 0.88 mmol), and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was not complete, so additional lithium hydroxide (5 mg, 0.21 mmol) was added, and the mixture was stirred for 6 h. Analysis by LC/MS indicated that the reaction was still not complete, so additional lithium hydroxide (15 mg, 0.63 mmol) was added, and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was complete. The THF was stripped in-vacuo at room temperature, and the aqueous was freeze-dried to yield 270 mg of yellow powder. This material was used as-is in the next step. 1H NMR (500 MHz, CD3OD) δ ppm 3.72 (s, 2H) 7.54 (s, 1 H) 7.96 (s, 1 H).