Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH2:13]=O>C(NCC)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[C:9](=[CH2:13])[CH:10]=[O:11]
Reactant: C=O
Reactant: CC1(C)C2CCC(CC=O)C1C2
Solvent: CCNCC
Product: C=C(C=O)C1CCC2CC1C2(C)C
Yield: 86.4 %

Procedure:
In a similar manner to Example 49, 342 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde at a purity of 97% (1.99 moles), 178 g of 37% formaldehyde (2.2 moles), 7.3 g of diethylamine (0.1 mole), and 0.8 g of BHT were refluxed for 1.5 hours. After the usual work-up, 370 g of crude propenal was distilled to afford 317 g of purified product (89% yield). BP 75° C./0.5 mmHg; 1H-NMR (300 MHz), δ 0.92 (3H, s), 1.23 (3H, s), 1.47-2.40 (8H, m), 3.1 (1H, t, J=8.91 Hz), 5.91 (1H, s), 6.20 (1H, s), 9.50 (1H, s); 13C-NMR (75 MHz), δ 20.06, 20.92, 23.88, 26.76, 28.03, 32.82, 40.08, 41.32, 44.34, 131.53, 155.46, 194.97; IR (Neat), 2960, 2700, 1690, 940 cm-1 ; MS (m/e), 177 (M+ -1), 163, 145, 135, 121, 107, 91, 79, 41 (Base);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(NNC(=O)C(F)(F)F)cc1

Procedure:
2-(4-Nitrophenyl)-1-trifluoroacetylhydrazine (2.5 g, 0.01 mole) and platinum oxide (84%, catalytic amount) were mixed in ethanol (100 ml) and ethyl acetate (100 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a brown semisolid. Yield 2.0 g (91%), no m.p. was taken on this material. Spectral data verified its structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16]C)=[O:15])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Na+].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(CC(=O)O)ccc2c1

Procedure:
A mixture of 25 g. of methyl 6-methoxy-2-naphthylacetate, 15 g. of sodium carbonate, 200 ml. of methanol, and 25 ml. of water are stirred for 24 hours. The reaction mixture is then acidified with 200 ml. of 2 N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate, and evaporated to yield 6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].CO[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:11]>>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][N:2]([CH3:1])[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:11]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCC(O)CO
Product: CN(CC(O)CO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 9 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methylamino-propane-1,2-diol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (9%) as sticky yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:24](#[N:27])[CH:25]=[CH2:26]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:25](=[CH2:26])[C:24]#[N:27])=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(-c2ccccc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.68 g.).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Agent: [Pd]
Product: CC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12

Procedure:
The preparation was carried out analogously to Example 46A by Pd/C-mediated hydrogenation starting with 3.5 g (about 9.72 mmol) of 8-(benzyloxy)-N-[(2R)-1-hydroxybutan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide. This gave 1.2 g (58% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([O:20][CH3:21])[CH:19]=2)[NH:16][CH2:15][CH2:14][CH2:13]3)=[CH:4][N:3]=1>[Pd].C1(C(C)C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([O:20][CH3:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc2c1NCCC2
Agent: [Pd]
Solvent: CC(C)c1ccccc1
Product: COc1cc(Cc2cnc(N)nc2N)cc2cccnc12
Temperature: 150 °C

Procedure:
The product of Example 2 was oxidised using 20% palladium on charcoal in 50 ml of cumene, by heating at 150° C. for 21 hours. After the catalyst was removed and the solvent evaporated, the residue was purified on a silica gel column which was eluted with methylene chloride:methanol/19:1. This produced 0.51 g (35%) of the title compound, which melted at 285°-287° after recrystallisation from betamethoxyethanol. Anal. Calcd. for C15H15N5O: C, 64.04; H, 5.37; N, 24.89. Found: C, 63.88; H, 5.37; N, 24.84.
Reaction SMILES: [F:1][C:2]([F:14])([CH:11]([F:13])[F:12])[CH:3](O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([F:14])([CH:11]([F:12])[F:13])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)C(F)(F)C(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)/C=C/C(F)(F)C(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
Ethyl 4,4,5,5-tetrafluoro-3-hydroxy-pentanoate (22.9 g, 0.105 mol) was mixed with phosphorus pentoxide (7.5 g, 0.053 mol) and the resulting mixture was stirred at 80° C. for two hours. The product was isolated by vacuum distillation (53 mbar, 92° C.) to yield 15.9 g of a liquid (0.08 mol, 76%) that was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([NH:21][CH:22]=[O:23])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([NH:21][CH:22]=[O:23])=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(NC=O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(NC=O)cc2)C(=O)OC1=O
Reaction time: 0.67 h

Procedure:
To a boiling solution of 2.67 g. (0.0123 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 50 ml. of methanol is added 1.8 g. (0.0132 m.) of p-aminoformanilide. Additional methanol is added (30 ml.) and reflux is continued for 40 minutes. The reaction mixture is filtered and the solid recrystallized to yield 5-acetyl-3-[1-(p-formamidophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6 (3H)-dione, m.p. 247°-248° C. (dec.).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:10]([O:27][C@H:28]1[CH2:32][CH2:31][C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[C@@H:29]1[CH2:43][O:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N.CO.ClCCl>N1C=CC=CC=1>[Si:10]([O:27][C@H:28]1[CH2:32][CH2:31][C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH:42][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:29]1[CH2:43][O:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:23]([CH3:26])([CH3:24])[CH3:25])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@H](n2cnc3c(N)ncnc32)[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H]1CC[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Benzoyl chloride (0.28 g, 0.231 ml, 2.0 mmol) was added dropwise to a cooled (ice-water bath) solution of compound 61 (0.97 g, 1.33 mmol) in anhydrous pyridine (10 ml). The bath was removed and reaction was stirred overnight, then cooled (ice-water bath) and treated with 2.5 ml of 7 N NH3/MeOH (added over 5 min). The reaction was removed from the bath, stirred under argon for 3 h to decompose the bis-benzoylated by-product and then concentrated in vacuo. The resultant residue was diluted with EtOAc and washed with 10% citric acid, saturated NaHCO3, saturated NaCl, dried over MgSO4 and concentrated in vacuo. The obtained material was chromatographed on silica eluting with 1:1 ethyl acetate: dichloromethane to give N-benzamide 62 (0.98 g, 88% yield) as a white sold foam.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[OH-].[K+].[CH3:9][O:10][CH2:11][CH2:12]Br>CS(C)=O.[Cl-].[Na+].O>[CH3:9][O:10][CH2:11][CH2:12][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: COCCBr
Reactant: Nc1cc[nH]n1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminopyrazole (2 g, 23 mmol) were dissolved in 15 ml DMSO. Potassium hydroxide (3.8 g, 69 mmol) was added and the mixture was stirred at room temperature for 30 min. 2-Bromoethyl methyl ether (3.2 g, 23 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was poured into 100 ml brine and extracted three time with 100 ml ethyl acetate. The organic phases were pooled, dried with sodium sulfate and evaporated. The two regiosomers were separated by flash chromatography and the title compound was obtained as a brown oil (0.824 g, 25%), MS (ISP): m/e=142.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
cis-4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (3.6 g, 8.16 mmol) was dissolved in dry DCM (150 mL) and cooled to 5° C. Methanesulfonyl chloride (0.94 ml, 12.2 mmol) and diisopropylethylamine (4.26 ml, 24.4 mmol) were added sequentially. After 2 h, the reaction was quenched with cold water (10 mL) and warmed to room temperature. The solution was partitioned between DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield a yellow solid. The residue was then chromatographed (silica, 100:1 DCM/MeOH) and washed with cold methanol to yield a pale yellow solid as methanesulfonic acid cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl ester (3.90 g, 7.50 mmol, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH:11]C(=O)C)[C:5]=1[N+:15]([O-:17])=[O:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(Br)ccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid methyl ester (iii, 5.53 g, 17.42 mmol) and BF3.Et2O (10.0 mL, 78.91 mmol) in MeOH (100 mL) was heated to reflux for 2 h and cooled to room temperature. The reaction mixture was neutralized with solid NaHCO3 and the solvent was removed under reduced pressure. The solid residu was dissolved in EtOAc (400 mL) and washed with H2O (3×200 mL), brine (1×200 mL), and dried with Na2SO4. The solvent was removed under reduced pressure to yield the desired product iv as an orange solid (4.74 g, 100%). 1H NMR (CDCl3): δ 7.40 (d, J=9.3 Hz, 1H), 6.70 (d, J=9.3 Hz, 1H), 6.09 (br s, 2H), 3.90 (s, 3H). Anal. Calcd for C8H7BrN2O4: C, 34.93; H, 2.57; N, 10.18. Found: C, 35.08; H, 2.49; N, 10.06.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.B([O-])=O.[Na+].[OH-].[K+].[CH2:14](O)[CH3:15]>Cl>[CH2:14]([O:6][CH:4]1[NH:5][C:1](=[O:7])[CH2:2][CH2:3]1)[CH3:15]
Reactant: CCO
Reactant: O=C1CCC(=O)N1
Agent: Cl
Agent: O=B[O-]
Agent: [K+]
Product: CCOC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
At 0° C., 9.91 g of succinimide were charged initially in 415 ml of ethanol and a total of 5.53 g of sodium boranate was added a little at a time. At this temperature, every 15 minutes 2 to 3 drops of 2N ethanolic hydrogen chloride were added dropwise over 4½ hours. Subsequently, the mixture was acidified to pH 3 using more acid. After stirring for 1 hour at 0° C., the mixture was neutralized using 1% strength ethanolic potassium hydroxide solution and the mixture was stirred for a further 15 minutes and evaporated. The residue was taken up in water and extracted three times with dichloromethane. After drying over sodium sulphate and concentrating, 7.16 g (55% of theory) of γ-ethoxy-γ-butyrolactam were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:13]([OH:15])=O)=[C:10](C)[N:11]=2)[CH:2]=1.[NH2:16]C1C=CC=CC=1>S(Cl)(Cl)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:13]([NH2:16])=[O:15])=[CH:10][N:11]=2)[CH:2]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc(-c2cccnc2)sc1C(=O)O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnc(-c2cccnc2)s1
Temperature: 82 °C

Procedure:
2-(3-Pyridyl)-4-methylthiazole-5-carboxylic acid (0.61 g, 2.8 mmol) was dissolved in thionyl chloride (2 mL) and the mixture was stirred with heating (82° C., 3 hours). Upon cooling, the solvent was removed and the residue was dried under high vac. The acid chloride was then suspended in 5 mL of pyridine and added to a microwave vial charged with 2-(3-morpholinomethyl)imidazo[2,1-b]thiazol-6-yl)aniline (0.87 g, 2.8 mmol). The reaction was subjected to microwave irradiation (160° C., 15 min). The solution was triturated with methanol, and the resulting solid was filtered and washed with additional methanol. The solid was dried to afford 0.97 g (68%) of 4-methyl-N-(2-(3-morpholinomethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)-2-(pyridin-3-yl)thiazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12.[H-].[Na+].[CH3:15]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:15])[CH:10]=[C:11]([I:12])[C:3]=12
Reactant: CI
Reactant: Cc1cc(Cl)c2c(I)c[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c2c(I)cn(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask under N2 gas, 4-chloro-3-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine (D12) (1.48 g, 5.06 mmol) was dissolved in THF (25 mL) and cooled to 0° C. To this was added NaH (0.405 g, 10.12 mmol) portion wise. After 30 minutes of stirring, methyl iodide (0.633 mL, 10.12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 mins and at RT for 1 hour.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1.[Br:19]Br>ClCCl>[Br:19][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:18][C:8]=2[C:9]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrBr
Reactant: OCCc1ccc2occ(-c3ccccc3)c2c1
Solvent: ClCCl
Product: OCCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Temperature: 15 °C

Procedure:
The product from step A is dissolved in 200 ml. of dichloromethane, the solution is cooled to 5° C., and 9.16 g. (0.0573 mole) of bromine in 50 ml. of dichloromethane is added dropwise. The solution is allowed to warm to 15° C., then evaporated to provide a green residue of 2-bromo-5-(2-hydroxyethyl)-3-phenylbenzofuran. The structural assignment is confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[N+:14]([O-])=O)([CH3:3])=[CH2:2].[H][H]>CO.[Pd]>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(C)C)cc1OC
Yield: 94.5 %

Procedure:
1-Isopropenyl-4,5-dimethoxy-2-nitro-benzene (446 mg, 2.0 mmol) was dissolved in 50 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (4:1 Hexanes/Ethyl Acetate) to give 2-isopropyl-4,5-dimethoxy-phenylamine (369 mg, 94.6%) as a tan oil.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])N.C(=O)=O.N([O-])=O.[Na+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=[O:27]>O.CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:25]2[O:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=C=O
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2ccc(C=O)o2)cc1OC
Reaction time: 192 h
Yield: 26.9 %

Procedure:
A 12 l. four-necked flask equipped with a stirrer, a thermometer and a dropping funnel was charged with water (5 l.). Hydrochloric acid (500 ml) was introduced dropwise. 3,4-dimethoxyaniline hydrochloride (379 g, 2.0 moles) was introduced. This mixture was cooled to -5° C. with a mixture of dry ice and acetone. A solution of sodium nitrite (200 g, 2.9 moles) in water (1600 ml) was introduced dropwise maintaining the temperature at -5° to 0° C. This was followed by the addition of furaldehyde (384 g, 4.0 moles) at -5° C. as fast as possible. A solution of CuCl2.2H2O (112 g) in water (500 ml) was introduced. Stirring was continued for 8 days at ambient temperature. The contents of the flask was extracted with ether (3×3 l.). The combined extracts were dried over MgSO4 overnight. The mixture was filtered and the drying agent was washed with anhydrous ether. The solvent was removed in vacuo. The excess furfural was removed by using an oil pump and a water bath having a maximum temperature of 63° C. The residue was triturated with a minimum amount of isopropanol and ice cooled. The semi-solid was filtered off and washed with isopropanol. The obtained solid was stirred with fresh isopropanol (500 ml) and filtered to give 125 g of the product (27%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>O>[CH2:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]1[O:22][CH2:20]1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC1CO1
Yield: 60 %

Procedure:
To a solution of 3-chloro-2-hydroxypropyl hexadecyl ether (10 g, 0.0311 moles in 20 mls water at 90° C. under argon was added a 50% solution of sodium hydroxide (1.37 g, 0.0343 moles) in 10 mls water over 15 minutes. The reaction was heated under the same conditions for 3 additional hours. Sample was purified by distillation (yield=60%). Upon cooling a white solid formed.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10]O>>[NH2:9][C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4][N:10]=1
Reactant: N#Cc1ccccc1N
Reactant: NO
Product: Nc1n[nH]c2ccccc12

Procedure:
is prepared by reacting anthranilonitrile with hydroxylamine, and the amidoxime thus prepared is then reacted with ester to produce a 3-aminoindazole of the following formula (3):
Reaction SMILES: CN(C1C=CC=CC=1)C(Cl)=O.[CH3:12][N:13]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:12][N:13]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44][C:23]([NH:22][C:20]([N:13]([CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:21])=[S:24])=[CH:45][CH:46]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CN(C(=O)Cl)c1ccccc1
Agent: CN(C(=O)N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(C)c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(Methylanilino)methanoyl isothiocyanate was prepared using commercially available N-methyl-N-phenylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Methylanilino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 63%).