Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:15][S:14][CH:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NO)C(=O)C(C)Br
Reactant: OCCS
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NO)C(=O)C(C)SCCO
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A solution of ethyl 4-bromo-2-hydroxyimino-3-oxovalerate (50 g.) in chloroform (100 ml) was added dropwise to a stirred solution of 2-mercaptoethanol (20.5 g.) and triethylamine (26.6 g.) in chloroform (100 ml) at room temperature over 1.5 hours, and stirred at the same temperature for 2 hours. After removing chloroform from the resultant solution in vacuo, water (600 ml) and ethyl acetate (600 ml) were added to the residue and adjusted to pH 1.0 with conc.hydrochloric acid. The ethyl acetate layer was separated, washed with water (200 ml), dried over magnesium sulfate and then concentrated in vacuo to give ethyl 4-(2-hydroxyethylthio)-2-hydroxyimino-3-oxovalerate (38.8 g.).
Reaction SMILES: O[C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:18][C:2]([CH3:19])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17]
Reactant: CC(C)(O)CCCCc1ccc2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=CCCCc1ccc2ccccc2c1O
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A solution of the compound of Example 119 (0.45 g, 0.002 mole) and p-toluenesulfonic acid (4-5 crystals) in toluene (20 mL) was heated at reflux with azeotropic removal of water. After 18 hours, the cooled solution was washed with saturated aqueous sodium bicarbonate and evaporated to provide the title compound (0.45 g, 100%) as an oil; mass spectrum: m/z 240.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1)[S:39]([C:32]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=1[CH3:43])(=[O:41])=[O:40]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(I)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2Cl)c2ccc(I)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-(4-iodophenyl)-amine (3.00 g, 6.76 mmol) in 4 mL methylene chloride was added triethylamine (2.84 mL, 20.3 mmol) and 2-mesitylenesulfonyl chloride (2.96 g, 13.5 mmol). The reaction mixture was stirred at room temperature overnight. Additional triethylamine (1 mL, 7.15 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. DMAP was added and the reaction mixture was allowed to stir at room temperature for three days. Additional methylene chloride (2 mL), triethylamine (1 mL, 7.15 mmol) and 2-mesitylenesulfonyl chloride (1.00 g, 4.57 mmol) were added. The reaction mixture was stirred at 30° C. overnight. Additional triethylamine (2.84 mL, 20.3 mmol) and DMAP were added and the reaction was stirred at 30° C. overnight. Additional 2-mesitylenesulfonyl chloride (0.54 g, 2.47 mmol) was added and the reaction mixture was stirred at 30° C. overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue afforded 2.30 g (54%) of the title compound of Step B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33]>C(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxylamine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8 g, 61% yield) as a white solid which was used directly in the next step.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>CC#N>[CH3:6][C@H:3]([CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)[CH2:4][OH:5]
Reactant: C[C@@H](CO)CBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 72 °C
Yield: 64.7 %

Procedure:
(S)-3-Bromo-2-methylpropan-1-ol (6.2 g, 40 mmol) was dissolved in dry CH3CN (100 mL) and dry, pulverized K2CO3 (10.4 g, 75 mmol) was introduced followed by 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50 mmol). The reaction mixture was heated at 72° C. for 20 h, cooled and filtered. The filtrate was evaporated to an oil, which was applied to a column of silica gel. Elution initially with hexanes, gradually increasing polarity to a mixture of hexanes/ethyl acetate (3:2) as eluent, provided the title compound (7.56 g, 64%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.Cl.[F:12][C:13]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][NH:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[C:13]([F:12])[C:21]([F:22])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Fc1ccc2c(c1F)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F

Procedure:
0.50 g (3.2 mmol) 2-chloroisonicotinic acid, 0.63 mg (3.3 mmol) 4,5-difluoroindoline-hydrochloride, 0.91 mL (6.5 mmol) TEA and 1.1 g (3.4 mmol) TBTU in 10 mL DMF were stirred overnight at RT. Then the reaction mixture was poured onto 200 mL of 15% potassium carbonate solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[CH:13][CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:21]I.Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[C:13]([CH3:21])[CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1Nc2cc(Cl)ccc2Cn2cccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2n(c1)Cc1ccc(Cl)cc1NC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2.33 g of 8-chloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one in 50 mL of methylene chloride is added 5.33 g of aluminum trichloride in small aliquots over a 30 minute period. During this time the temperature of the reaction is maintained below 30°. To this reaction mixture 4 mL of methyl iodide is added, and the reaction is allowed to stir for 48 hours at room temperature. The reaction mixture is diluted with 24 mL of methanol and then poured into 150 mL of dilute hydrochloric acid. The methylene chloride layer is separated and washed with 200 mL of brine and saturated aqueous sodium bicarbonate. The methylene chloride extract is dried over anhydrous magnesium sulfate and evaporated to dryness to yield 8-chloro-2-methyl-10,11-dihydro-5-H-pyrrolo-[2,1-c][1,4]benzodiazepine-11-one, which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1I)[CH3:2].C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1nc(N)sc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1nc(N)sc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a stream of Ar the above prepared 4-ethyl-5-iodo-thiazol-2-ylamine (1.67 g, 6.57 mmol) was dissolved in 40 mL of acetonitrile and treated successively with triethylamine (2.73 mL, 3 eq.), Cul (0.125 g, 0.1 eq.), (Ph3P)2PdCl2 (0.46 g, 0.1 eq.) and ethynyltrimethylsilane (2.73 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 15 h at ambient temperature. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded finally 0.598 g of the title compound as brown viscous oil, contaminated with some des-iodo-compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C([Li])CCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH2:2][CH2:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1cc2c(cc1OCC1CC1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(OCC3CC3)ccc3c2OCO3)OC1(C)C
Reaction time: 2 h

Procedure:
A stirred solution of 5-cyclopropylmethoxy-benzo[1,3]dioxole from example B.b1 (38.44 g; 200.0 mmol) in dry THF (500 mL) is cooled to −40° C. before n-butyl lithium (138.0 mL; 1.6 M solution in hexane; 220 mmol) is slowly added via syringe. After complete addition, stirring is continued at −40° C. for two hours. At −78° C. neat 2-iso-propoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (40.95 g; 220.0 mmol) is added via syringe and stirring is continued at −78° C. for two hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=[O:14])=[CH:4][C:3]=1[CH3:18].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][OH:14])=[CH:4][C:3]=1[CH3:18]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(-c2oncc2CO)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 5-(4-chloro-3-methylphenyl)isoxazole-4-carboxylate (8.50 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.5 M toluene solution, 47 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol (6.13 g, yield 86%) as colorless crystals, which were recrystallized from ethyl acetate-hexane to give a colorless needle. melting point: 92–93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[C:14]([NH2:15])=[O:13]
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Yield: 22.2 %

Procedure:
6-Amino-3,4-dihydrocarbostyril (1.6 g) is dissolved in a mixture of acetic acid (5 ml) and water (10 ml), and thereto is added dropwise a solution of sodium cyanate (1.3 g) in water (9 ml) with stirring at room temperature. The mixture is stirred at the same temperature for 1 hour. After the reaction, the resulting precipitate is separated by filtration, washed with water, purified by silica gel column chromatography (solvent; chloroform:methanol=50:1), and recrystallized from dimethylformamide-water to give 6-ureido-3,4-dihydrocarbostyril (0.45 g) as colorless needles, m.p.>300° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I:11]N1C(=O)CCC1=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[I:11][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)c1ccc(O)c(I)c1
Yield: 85.3 %

Procedure:
A solution of 4-isopropylphenol (500 mg, 3.67 mmol), N-iodosuccinimide (838 mg, 3.72 mmol) and p-TsOH (70 mg, 0.37 mmol) in CH2Cl2 (25 mL) was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried and evaporated to give 820 mg of 2-iodo-4-isopropylphenol (85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=7.03 Hz, 6 H) 2.82 (spt, J=6.95, 6.65 Hz, 1 H) 6.92 (d, J=8.53 Hz, 1 H) 7.11 (dd, J=8.28, 2.01 Hz, 1 H) 7.50 (d, J=2.01 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[NH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.C1C(=O)N([Br:28])C(=O)C1.O>C1COCC1>[Br:28][C:17]1[CH:16]=[C:15]([C:18]#[N:19])[NH:14][C:13]=1[C:11]1[CH:10]=[CH:9][C:4]2[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:20])([CH3:1])[C:3]=2[CH:12]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To 4,4-dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.625 g, 2.3 mmol, 1 eq) in THF (anhydrous, 60 mL) was added NBS (0.46 g, 2.5 mmol, 1.1 eq) at −78° C. After 1 hour, the reaction was warmed to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with aqueous 10% sodium bisulfite solution (50 mL), water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave the product (40 mg, 5%) as a white solid. The filtrate (0.5 g) was placed aside. 1H NMR (300 MHz, d6-DMSO): δ 1.64 (s, 6H), 6.98 (d, 1H, J=8.2 Hz), 7.19 (d, 1H, J=1.4 Hz), 7.57 (s, 1H), 7.62 (dd, 1H, J=1.4, 8.3 Hz), 10.43 (s, 1H), 12.91 (s, 1H). MS (ESI) [M−H]−m/z 344/346. Anal. calcd. for C15H12BrN3O2: C, 52.04; H, 3.49; N, 12.14. Found: C, 51.4; H, 3.57; N, 11.59.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].CN(C)C=O.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1>O>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[CH:12]=[O:13])[N:24]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3ccccc3c2C=O)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 47.7 %

Procedure:
8.6 g (0.05 mol) of 2-hydroxynaphthalene-1-aldehyde are introduced into 50 ml of dry dimethylformamide and admixed by stirring, at 0°-5° C., with 1.5 g (0.05 mol) of 80% strength sodium hydride added a little at a time. 10.9 g (0.05 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are then added at room temperature, and the mixture is heated to 90° C. and stirred at that temperature for 6 hours. The solution thus obtained is poured into water. The aqueous mixture is extracted with methylene chloride, carefully washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product is further purified by stirring out with cold toluene, leaving 7.4 g of 2-(4,6-dimethoxypyrimidin-2-yloxy)naphthalene-1-aldehyde of m.p. 123°-125° C.
Reaction SMILES: C1(=O)[O:6][C@H:4]([CH3:5])[CH2:3]O1.[N:8]1[C:16]([NH2:17])=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[N:10][CH:9]=1.[OH-].[Na+]>CN(C)C=O>[OH:6][C@H:4]([CH3:5])[CH2:3][N:12]1[CH:13]=[N:14][C:15]2[C:11]1=[N:10][CH:9]=[N:8][C:16]=2[NH2:17]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: C[C@@H]1COC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@@H](O)Cn1cnc2c(N)ncnc21

Procedure:
To a reaction vessel containing inert atmosphere, e.g., nitrogen, was added carbonate (A), adenine, N,N-dimethylformamide (DMF) and catalytic amount of base such as sodium hydroxide, then (R)-9-(2-hydroxypropyl)adenine (B) was obtained;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7])=[CH2:2].[CH2:12]([O:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:2]=[CH:1][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([NH2:8])=[O:7])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][C:29](=[O:34])[NH:30][S:31]1(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1cccc(C(N)=O)c1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1cccc(C=Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 3-vinylbenzamide (32 mg, 0.22 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), Pd(OAc)2 (20 mg, 0.09 mmol) and triethylamine (0.256 mL, 1.84 mmol) in MeCN (2 mL) is heated in a microwave apparatus at 120° C. for 25 min. The mixture is filtered over Celite and washed with MeCN. The filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)[CH:20]=[CH:19][C:18]=1[NH2:29]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:29][C:18]1[CH:19]=[CH:20][C:21]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)=[CH:22][C:17]=1[O:16][CH3:15])=[O:8])=[O:5]
Reactant: COc1cc(-c2nnc(C)[nH]2)ccc1N
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(C)[nH]2)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 30 mg of 2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction, stirred with isopropanol and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: COc1cccnc1Cl
Temperature: 50 °C

Procedure:
To a solution of 2-chloro-pyridin-3-ol (100 g) in DMSO (1 L) was added potassium carbonate (320 g). Methyliodide was added dropwise. The reaction mixture was heated to 50° C. overnight. The reaction mixture poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the desired compound.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)[CH:9]=1>C1COCC1.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH:9]=1
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
Lithium hydroxide (0.427 g, 17.8 mmol) was added to a stirred suspension of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.40 g, 8.92 mmol) in 20 mL of a 4:1 mixture of THF/ethanol. The mixture was stirred under nitrogen for 3 days at ambient temperature. The pH of the mixture was adjusted to neutral (by the addition of aqueous mineral acid) inducing a heavy precipitation of off-white colored solids. The solids were isolated by filtration and dried under reduced pressure to give the desired product (2.0 g; 93%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1)(=[O:3])[CH3:2].[H][H]>[C].[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1ccc(N)c(C(F)(F)F)c1
Yield: 121.1 %

Procedure:
In the ethyl acetate (30 mL) solution of 4-nitro-3-trifluoromethyl-phenoxyethyl acetate (3.24 g (theoretical amount: 2.83 g, 9.66 mmol) which had been obtained in 1), 10% palladium carbon (0.3 g) was added and hydrogen was added. After the catalyst had been separated by filtration, the solvent was removed by distillation under reduced pressure and crude 4-amino-3-trifluoromethyl-phenoxyethyl acetate (BB03, 3.08 g (theoretical amount: 2.54 g) 100%) was obtained as oily matter.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](Br)[CH:24]=[CH:23][N:22]=1.C(O[Na])CCC.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[CH:24]=[CH:23][N:22]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: COc1cc(Br)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCCO[Na]
Solvent: Cc1ccccc1
Product: COc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 90 °C
Yield: 51 %

Procedure:
Benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (1.43 mmol, 1.0 eq.), 2-methoxy-4-bromopyridine and BuONa (411 mg, 4.29 mmol, 3.0 eq.) were taken up in toluene (20 ml) and degassed with argon. Xantphos (50 mg, 0.085 mmol, 0.06 eq.) and Pd2(dba)3 (26 mg, 0.028 mmol, 0.02 eq.) were then added and the mixture was heated for 16 hours at 90° C. After monitoring by TLC, the reaction mixture was concentrated and the residue was taken up in DCM (100 ml), washed with water and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 0.5% MeOH in DCM). Yield: 51% (260 mg, 0.732 mmol)