Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:22][C:21]=1[CH:31]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:22][C:21]=2[CH3:31])[CH2:15][CH2:14]1
Reactant: Cc1nc(-c2ccccc2)[nH]c1C=O
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of benzooxazol-2-yl-piperidin-4-yl-amine (65.2 mg, 0.3 mmol, 1.0 equiv; free amine of intermediate D) and 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde (61.5 mg, 0.33 mmol, 1.1 equiv; [CAS RN 68282-50-8] prepared as described in L. A. Reiter J. Org. Chem. 1987, 52, 2714-2726) in ethanol (2 mL) was added acetic acid (54.1 mg, 0.9 mmol, 3.0 equiv) and the reaction mixture heated under microwave irradiation to 100° C. After 10 min, sodium cyano borohydride (24.5 mg, 0.39 mmol, 1.3 equiv) was added and the mixture heated under microwave irradiation to 100° C. for an additional time period of 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.0 mg (15%) of the title compound. MS (ESI): 388.3 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CN2CCOCC2)n1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [6-(morpholin-4-ylmethyl)pyridin-2-yl]carbamate (114 mg, 0.39 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol) at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate was added to adjust to pH˜9. The mixture was extracted with ethyl acetate (3×), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 6-(morpholin-4-ylmethyl)pyridin-2-amine that was used without further purification. MS ESI calc'd for C10H16N3O [M+H]+ 194. found 194. 1H NMR (500 MHz, DMSO-d6) δ 7.32 (t, J=7.7 Hz, 1H), 6.52 (d, J=7.2 Hz, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.90 (s, 2H), 3.63-3.49 (m, 4H), 3.40-3.25 (m, 2H), 2.41 (s, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)=[CH:5][C:4]([CH3:19])=[N:3]1.[Cl:20]/[CH:21]=[CH:22]/[CH2:23][O:24][NH2:25]>CO>[Cl:20][CH:21]=[CH:22][CH2:23][O:24]/[N:25]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:19])[CH:5]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: NOC/C=C/Cl
Reactant: CCC(=O)C1C(=O)CC(c2cc(C)nn2C)CC1=O
Solvent: CO
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2cc(C)nn2C)CC1=O

Procedure:
To 10 ml of a solution of 5.60 g (21.3 mmols) of 5-(1,3-dimethyl-1H-pyrazol-5-yl)-2-propionylcyclohexane-1,3-dione in methanol was added 57 ml (21.7 mmols) of 0.38 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 10 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 6.84 g of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCN2CCOCC2)cc1
Yield: 55.4 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (45 mg, 0.09 mmol), 4-(3-chloropropyl)morpholine hydrochloride (19 mg, 0.10 mmol) and K2CO3 (25 mg, 0.18 mmol) in DMF (1 mL) was stirred at 60° C. for 18 h. The reaction mixture was partitioned between EtOAc (10 mL) and water (5 mL), the organic layer was separated and washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and loaded onto a column of SCX (5 g). The column was washed with MeOH and then the product was eluted with 1% NH3 in MeOH, removal of the solvents in vacuo afforded ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-morpholinopropoxy)phenyl)-1H-pyrrole-2-carboxylate (37) (32 mg, 57%) as a yellow oil: m/z 642 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.47-7.42 (m, 2H), 7.41-7.30 (m, 8H), 7.10-7.05 (m, 2H), 6.99-6.91 (m, 2H), 5.11 (s, 2H), 4.96 (s, 2H), 4.04-3.95 (m, 4H), 3.59-3.52 (m, 5H), 2.72-2.67 (m, 6H), 2.44-2.38 (m, 3H), 2.37-2.32 (m, 5H), 1.92-1.81 (m, 2H), 1.00 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: CON
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-tert-Butyl-1-indanone (13.41 g, 71.23 mmol) and methoxyamine hydrochloride (6.68 g, 80 mmol) were dissolved in pyridine (75 ml) and stirred at ambient temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between water and diethyl ether (X2). The combined organic layers were washed with 1N aqueous hydrochloric acid, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3Cl)[N:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:27].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]3=[O:27])[N:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2ncnc(Cl)c2[nH]1
Agent: [K+]
Product: COc1cc(OCc2ccccc2)ccc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
Prepared analogously to Example 16 from 8-(4-benzyloxy-2-methoxy-phenyl)-6-chloro-purine by reaction with 40% potassium hydroxide solution.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (12.8 mg, 0.032 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 22.5 mg, 0.096 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (30.6 mg, 0.160 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.6 mg, 0.160 mmol), N-ethyl-N-isopropylpropan-2-amine (41.3 mg, 0.320 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (13.3 mg, 67.5%). LRMS (APCI pos): m/e 617 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[O:25][C:24]([CH2:26][NH2:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[O:25][C:24]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:23][CH:22]=1
Reactant: Cc1ccc(CN)o1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(C)o3)s2)c(C)[nH]c1=O
Yield: 93 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (5-methylfuran-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a solid (93% yield). LC/MS: RT 2.90 min; m/e 393 (M+H); 1H NMR (δ, ppm): 11.75 (1H, br s), 8.32 (1H, br s), 7.48 (1H, d), 729 (1H, s); 7.10 (1H, d); 6.07 (1H, d), 5.92 (1H, d), 4.05 (2H, s), 2.41 (2H, q), 2.30 (3H, s), 2.15 (3H, s), 1.10 (3H, t).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[Cl:12][C:11]1[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:13][CH2:14][S:15][C:6]1=[C:5]([C:16]([OH:18])=[O:17])[C:4]2=[O:19]
Reactant: O=C(O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1c2n(c3ccc(Cl)c(N4CCNCC4)c3c1=O)CCS2

Procedure:
A mixture of 500 mg (1.58 mmol) of 6,7-dichloro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)quinoline-4-carboxylic acid, 1.0 gram (11.6 mmol) of piperazine, and 20 ml of pyridine was heated to reflux for ten hours. The content was then concentrated under reduced pressure, water was added to the residue, insoluble matters were taken out by filtration, washed with water, dried, and recrystallized from dimethyl formamide to give the title compound. Yield was 420 mg (72.7 percent). Melting point: 244° to 245° C. (decomposition). Elementary analysis calculated as C16H16ClN3O3S.21/2 H2O: C 46.77, H 5.15, N 10.22; Found: C 46.66, H 4.90, N 9.81.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])=[O:6].[I:17]N1C(=O)CCC1=O.CO>C(Cl)(Cl)Cl>[I:17][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[O:15][CH:3]=1
Reactant: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(=O)c(I)coc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0 g, 90.37 mmol) in anhydrous chloroform (100 ml) at 0° C. was added N-iodosuccinimide (23.5 g, 99.22 mmol) and silica gel (40 g). The reaction mixture was stirred at 0° C. for 60 minutes, then the insoluble material filtered off. The filtrate was washed with aqueous sodium thiosulfate (0.5M, 2×50 ml), followed by brine (100 ml), then dried over sodium sulfate. The solvent was removed under reduced pressure, providing an orange solid. To this solid was added methanol (30 ml), and the mixture was sonicated, filtered, the solid washed with methanol (2×5 ml), and the solid dried under reduced pressure, to give 3-iodo-7-methoxychromen-4-one as a pale yellow solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.[I:24]I>O1CCCC1>[I:24][C:22]1[C:17]([C:16]#[N:23])=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: N#Cc1cccnc1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cnccc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,2,6,6-tetramethyl-piperidine (42.3 g, 0.3 mol) in 2 L of tetrahydrofuran was added butyllithium (120 mL, 2.5M, 0.3 mol) at −78° C. under N2 atmosphere. The mixture was stirred for 1 hour before a solution of nicotinonitrile (26 g, 0.25 mol) in 500 mL of tetrahydrofuran was slowly added, and the resulting mixture was stirred for 0.5 hour at −78° C. Then I2 (76.2 g, 0.3 mol) in 500 mL of tetrahydrofuran was added in a dropwise manner. After stirring for 2 hours, the mixture was quenched with 500 mL of ice-water. Tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted with ether. The organic phase was washed with brine, citric acid, brine, aqueous Na2S2O3 and brine again. After being dried over Na2SO4, the organic phase was concentrated and purified by using column chromatography on silica gel (petroleum ether:ethyl acetate, 10:1) to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15]O.[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[SH:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[S:23][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2
Reactant: OCc1cccc2cc(-c3nccs3)[nH]c12
Reactant: Cn1ccnc1S
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1SCc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A solution of [2-(1,3-thiazol-2-yl)-1H-indol-7-yl]methanol (0.095 g), 1-methyl-1H-imidazole-2-thiol (0.047 g) and tributylphosphine (0.251 g) in tetrahydrofuran (7 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.312 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.089 g, yield 66%) as colorless crystals.
Reaction SMILES: O.[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10](OCC)(OCC)[O:11]CC)[CH:3]1[O:5][CH2:4]1>C(O)(=O)C>[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][SiH2:10][OH:11])[CH:3]1[O:5][CH2:4]1
Reactant: CCO[Si](CCCOCC1CO1)(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: O[SiH2]CCCOCC1CO1
Temperature: 90 °C

Procedure:
In a three-necked flask equipped with a stirrer, dropping funnel and reflux condenser, 500 g water were adjusted with dilute acetic acid to a pH value of 4 to 4.5. 15 g glycidoxypropyl triethoxysilane were then added dropwise, the mixture being heated to 90° C. This temperature was maintained for 1 hour.
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9]C(OC)=O)=[C:6]([O:16][CH2:17][C:18]([O:20]CC)=O)[CH:5]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl>O1CCCC1>[CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH2:9][C:18](=[O:20])[CH2:17][O:16][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OCC(=O)OC)c(OCC(=O)OCC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCc1ccc2c(c1)OCC(=O)CO2
Temperature: 0 °C
Yield: 41.9 %

Procedure:
A solution of 69.0 g (234 mmol) of methyl 4-allyl-2-(ethoxycarbonylmethoxy)phenoxyacetate was added dropwise in the course of 2.5 h to a suspension of 12.0 g (500 mmol) of sodium hydride in 500 ml of tetrahydrofuran. The reaction mixture was then refluxed for 20 h and, after cooling, poured into 1.51 of ice water. The resultant mixture was acidified to pH 2 with 2N hydrochloric acid and extracted three times, each time with 2 l of ether. The combined ether extracts were dried over sodium sulfate, freed from solvent on a rotary evaporator and taken up into 400 ml of ethanol. 400 ml of 2N hydrochloric acid were added and the mixture was refluxed for 20 h. The mixture was then poured into 1.5 l of ice water, the product was extracted four times, each time with 1.5 l of ether, and the combined ether extracts were washed with 1 l of water and 100 ml of saturated sodium chloride solution. After drying over sodium sulfate, concentration on a rotary evaporator and flash chromatography (pentane/ether, 4:1, Rf=0.37) on silica gel, 20.0 g (42%) of 7-allylbenzo[b][1,4]dioxepin-3-one (1) were obtained as a colorless liquid. Odor: linear, very intensive marine-floral odor with nuances of ozone, watermelons and fatty aldehydes. -IR (film): ν=1502/1581/1436/1639 cm−1 (ν C═C, Ar), 1742 cm−1 (ν C═O), 1267/1305 cm−1 (ν ring), 1051 cm−1 (ν C—O—C). -1H-NMR (CDCl3): δ=3.30 (d, J=6.8 Hz, 2H, 1′-H2), 4.68 (d, J=7.2 Hz, 2-, 4-H2) 5.05-5.10 (m, 2H, 3′-H2), 5.92 (mc, 1H, 2′-H), 6.77-6.93 (m, 3H, 6-, 8-, 9-H). -13C-NMR (CDCl3): δ=39.15 (t, C-1′), 75.41/75.63 (2t, C-2,-4), 116.00 (t, C-3′), 120.67/120.73 (2d, C-6,-9), 123.73 (d, C-8), 135.94 (s, C-7), 136.88 (d, C-2′), 146.46 (s, C-9a), 148.00 (s, C-5a), 204.61 (s, C-3). -MS (EI): m/z (%)=91 (97) [C7H7+], 120 (25) [C7H4O2+], 161 (13) [M+-C2H3O], 175 (6) [M+-CHO], 204 (100) [M+].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
5-Amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (28.7 g) was heated at reflux in acetic anhydride (150 ml) for 8 hours. The reaction mixture was then evaporated to dryness and the solid residue was suspended in ethanol (250 ml). Saturated aqueous sodium bicarbonate solution was then added to give a pH of 8 and the suspension was then stirred magnetically for 16 hours. The solid obtained was separated by filtration, washed with water and dried, to give 5-acetamido-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (23.7 g), m.p. 222°-224° C., in the form of an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C([O:21][C:22]([C:24]1[N:29]2[C:30]([C:33](=[O:38])C(Cl)(Cl)Cl)=[CH:31][N:32]=[C:28]2[CH:27]=[CH:26][CH:25]=1)=O)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[C:22](=[O:21])[C:24]3[N:29]4[C:30](=[CH:31][N:32]=[C:28]4[CH:27]=[CH:26][CH:25]=3)[C:33]2=[O:38])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccc(Cn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1.47 g (12.0 mmol) of 4-aminobenzylamine and 1.68 g (13.0 mmol) of N,N-diisopropylethylamine was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for 7 hours at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and dried to afford 2.586 g of the desired compound (86.7%, a yellow crystals).
Reaction SMILES: C(C1C([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=NC(CC)=CN=1)C.Cl[C:23]1[C:24]([CH:32]2[CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([CH:29]2[CH2:31][CH2:30]2)[N:28]=1>>[CH:32]1([C:24]2[C:23]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:28][C:27]([CH:29]3[CH2:31][CH2:30]3)=[CH:26][N:25]=2)[CH2:34][CH2:33]1
Reactant: Clc1nc(C2CC2)cnc1C1CC1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2,5-dicyclopropylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.86–0.89, 2.00, 2.89, 3.11, 4.54, 5.17, 5.42, 6.22–6.24, 7.17–7.25, 7.64; MS (ESI+) for C19H21N3O m/z 308 (M+H)+.
Reaction SMILES: N[C:2]1C(Cl)=C(C(OCC)=O)C(C)=NC=1NCC.[NH2:18][C:19]1[C:20]([Cl:36])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]([CH3:30])=[N:23][C:24]=1[NH:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:25]1[C:24]2=[N:23][C:22]([CH3:30])=[C:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:20]([Cl:36])=[C:19]2[N:18]=[CH:2]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Reactant: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Product: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Yield: 83 %

Procedure:
By replacing 5-amino-6-ethylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester in Example 1 d with 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester, 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 83%, b.p. 190°-200°/0.01.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC([C:29]([NH2:31])=[NH:30])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]([NH2:31])=[NH:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(CCCCNC(=N)N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (0.1970 g, 0.46 mmol) in DMF (5 mL) was added 1H-pyrazole-carboxamidine hydrochloride (0.0681 g, 0.46 mmol) and DIPEA (0.48 mL, 2.76 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (20:1:1, then 10:1:1, then 1:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (20:4:1 CH2Cl2-MeOH—NH4OH) provided 0.1380 g (64%) of COMPOUND 196 as a white solid. 1H NMR (CDCl3) δ 1.49-1.53 (m, 2H), 1.65-1.69 (m, 2H), 2.17 (s, 6H), 2.70-2.75 (m, 4H), 3.12-3.14 (m, 2H), 3.87 (s, 4H), 7.10-7.14 (m, 2H), 7.41-7.44 (m, 2H), 8.34-8.39 (m, 2H). 13C NMR (CDCl3) δ 18.53, 23.14, 26.99, 41.30, 54.57, 58.09, 123.15, 133.48, 138.87, 146.21, 155.66, 158.02. ES-MS m/z 341.3 (M+H). Anal. Calcd. for C19H28N6.1.1CH2Cl2.1.8H2O: C, 51.77; H, 7.31; N, 18.02. Found: C, 51.50; H, 7.04; N, 18.31.