Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH3:6][O:7][Si:8]([O:15][CH3:16])([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][NH2:12]>Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>[CH3:6][O:7][Si:8]([O:13][CH3:14])([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][NH:12][C:3](=[O:5])[CH2:2][Br:1]
Reactant: O=C(O)CBr
Reactant: CO[Si](CCCN)(OC)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)CBr)(OC)OC
Reaction time: 2 h

Procedure:
Binder DNA oligonucleotide-derivatized porous silicon films were employed to test the selectivity and limits of detection of a contemplated sensor. For attachment of DNA, a trimethoxy-3-bromoacetamido-propylsilane linker was synthesized by reaction of bromoacetic acid with trimethoxy-(3-aminopropyl)silane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride in methylene chloride as solvent The linker product was purified by column chromatography on silica gel. The oxidized porous silicon samples were then contacted with a toluene solution of the linker for 2 hours. The resulting linker-bound substrate was thoroughly rinsed with pure toluene and methylene chloride, and dried for about 18 hours under reduced pressure.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[C:1]([NH:4][C:5]1[C:13]2[S:12][C:11]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(NC(C)=O)c2sc(N)nc12
Product: COc1ccc(NC(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 7-acetylamino-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride the title compound was obtained as a tan solid (25% yield), MS: m/e=359.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1[NH2:23])=[S:11])=[O:8]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1[NH:23][C:1](=[O:3])[CH3:2])=[S:11])=[O:8]
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC(C)=O)c1
Yield: 62 %

Procedure:
Acetyl chloride (4.53 g.; 0.058 mole) was added to a suspension of 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)-thiourea (16.0 g; 0.057 mol3) in dry toluene (230 ml) and the stirred mixture was refluxed for ninety minutes. During this time the solid gradually dissolved to give a slightly turbid solution. On cooling to laboratory temperature a solid separated which was filtered off and recrystallised to give 1-methoxycarbonyl-3-(2-acetamido-4-n-butylphenyl)thiourea (11.4 g), m.p. 173°-174° C. (with decomposition).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25]([Cl:27])=[N:24][CH:23]=[N:22][C:21]=3[N:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.O>ClCCl>[Cl:27][C:25]1[C:26]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[CH:17][CH:16]=3)=[CH:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: CC(C)n1cc(-c2ccc(N)cc2)c2c(Cl)ncnc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzenesulphonyl chloride (0.27 g) in dichloromethane (5 ml) was added dropwise with stirring to a solution of 5-(4-aminophenyl)-4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidine (0.40 g) and triethylamine (155 mg) in dichloromethane (15 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for one hour and then warmed to ambient temperature and stirred at this temperature for 18 hours. Water (20 ml) was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with sodium bicarbonate, dried, filtered and evaporated to give N-[4-(4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzenesulphonamide
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)[CH2:34][CH2:33]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a solution of 200 mg (0.65 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 5 ml of N,N-dimethylformamide (DMF), 270 mg (1.95 mmol) of potassium carbonate and 176 mg (1.30 mmol) of bromomethylcyclopropane were added at room temperature subsequently and stirred at about 50° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford a residue, which was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 231 mg (0.64 mmol) of the title compound as colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:8]=[N:7][CH:6]=1.[ClH:22]>>[ClH:22].[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][C:3]([OH:21])=[O:2])=[CH:6][N:7]=[CH:8]1
Reactant: COC(=O)Cc1cncn1Cc1ccc2ccccc2c1
Agent: Cl
Product: O=C(O)Cc1cncn1Cc1ccc2ccccc2c1
Temperature: 55 °C

Procedure:
2-[1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl]acetic acid methyl ester (0.92 g, 3.28 mmol ) was dissolved in 2.5M hydrochloric acid (50 ml) and heated at 55° C. for 3 h. After this time, the solution was evaporated in vacuo to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (35 g, 154 mol) in DMF (155 mL) was added potassium carbonate (32 g, 1.5 eq) at room temperature. The mixture was stirred at room temperature for 1 hr before being cooled with a water bath. Methyl iodide (19.2 mL, 2 eq) was added dropwised. The mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through a pad of celite, diluted with ethyl acetate (300 mL), washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (300 and 200 mL). The combined organic layers were washed with 10% Na2S2O3 solution (100 mL), water (3×200 mL) and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (2 wt. volumes) pad with 0-15% ethyl acetate in hexanes to afford the title compound (37.06 g, quantitative yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): 5.03 and 4.99 (2 br s, 2H), 4.51 (dd, J=9.5, 2.7 Hz) and 4.40 (dd, J=9.5, 3.3 Hz, 1H), 4.09 and 4.06 (2 br s, 2H), 3.73 (s, 3H), 3.01-2.92 (m, 1H), 2.65-2.60 (m, 1H), 1.47 and 1.42 (2 s, 9H).
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10](=[O:35])[CH:11]([OH:34])[C@@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH2:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.[N:43]1([C:49](Cl)=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[CH2:15]([O:14][CH2:13][C@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH:32][C:49]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:50])[CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH:11]([OH:34])[C:10](=[O:35])[NH:9][C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
N1-(1,1,3,3-tetramethylbutyl)-(3S)-3-[(2S)-2-amino-3-cyclohexylpropanoyl]amino-4-(benzyloxy)-2-hydroxybutanamide (360 mg, 0.7 mmole) was dissolved in DMF (7 mL), followed by addition of addition of triethylamine (205 ul, 1.5 mmole) and stirring under N2 for 15 min. 4-Morpholinecarbonyl chloride (93 ul, 0.8 mmole) was added. Stirring was continued overnight and DMF was removed under reduced pressure. The solution was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, Hexane/EtOAc with 10% MeOH, Rf=0.5) afforded N4-[(1S)-2-((1S)-1-[(benzyloxy)methyl]-2-hydroxy-3-oxo-3-[(1,1,3,3-tetramethylbutyl)amino]propylamino)-1-(cyclohexylmethyl)-2-oxoethyl]-4-Morpholinecarboxamide as a white solid (280 mg, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][OH:18])[CH3:13]>>[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][O:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH3:13]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
In a manner similar to that described in Example 231a, 3,4-difluoronitrobenzene (6.7 mL, 60.6 mmol, 1 equiv.) and 3-diethylamino-1-propanol (9 mL, 1 equiv.) are converted to the named compound as a brown oil (16.3 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH2:27])=[CH:22][CH:21]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:17])=[CH:26]3)[CH:8]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nccn5C)sc34)ccc2[nH]1
Yield: 68.9 %

Procedure:
7-Chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine (1.0 g, 4.0 mmol) and 2-methyl-5-aminoindole (732 mg, 5.0 mmol) were dissolved in 7 mL of t-butyl alcohol and 7 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight the reaction mixture was cooled and absorbed onto silica gel. Chromatography of the residue with 20% methanol:methylene chloride afforded 991 mg (69%) of [2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. 1H NMR (400 MHz, CD3OD) δ8.26 (d, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 7.48 (m, 2H), 7.39 (d, 1H), 7.04 (m, 2H), 6.20 (s, 1H), 3.33 (s, 3H), 2.43 (s, 3H). LC-MS: 360 (MH+); HPLC RT: 4.15 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][O:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)([O-:24])(=[O:23])=[O:21]
Reactant: O=Cc1ccccc1O
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1ccccc1C=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 50 %

Procedure:
A solution of 2-hydroxy-benzaldehyde (1.5 g, 12.16 mmol), potassium carbonate (8.4 g, 60.8 mmol) and toluene-4-sulfonic acid 3-methoxy-propyl ester (14.85 g, 60.8 mmol) in DMF (30 mL) is stirred at 50° C. for 3 h. The solvent is concentrated under reduced pressure, H2O is added, and the aqueous layer extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1 to 1/2) to afford the title compound together with 50% of remaining tosylate: MS 195.0 [M+H]. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.08 min. The mixture is further used as is in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH2:25]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O-:22])(=[O:21])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Agent: O[C@@H]1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 92 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (1.77 g, 10 mmol) in pyridine(30 ml) was added p-toluenesulfonyl chloride (9.53 g, 50 mmol) by portions at 0° C. After 90 h stirring at room temperature, water was added to the reaction mixture and the mixture was extracted with ether (150 ml). The extract was washed with water, brine, dried(Na2SO4), and concentrated to give 3.06 g (92%) of brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:16]([OH:18])=O)[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:25]C=2C=1.CN1CCOCC1.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:16](=[O:18])[NH2:25])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (6.4 g, 24.9 mmol) in dry THF (190 mL) was added HOBt (4.7 g, 34.8 mmol), NMM (3.83 mL, 34.8 mmol) and EDC (6.7 g, 34.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and quenched with concentrated ammonium hydroxide (16 mL). The reaction mixture was stirred at room temperature overnight. Excess of solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with 1N HCl, aqueous NaHCO3, brine and dried over Na2SO4. Evaporation of excess of solvent gave 6.4 g (100%) of (1-carbamoyl-2-isopropyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.62 (m, 1H), 1.00 (d, 3H), 1.05 (d, 3H), 1.25 (m, 3H), 1.45 (s, 9H), 3.05 (dd, 1H), 3.80 (dd, 1H), 6.70 (m, 1H); MS (APCI) m/z 257 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1.N[C:18]1[CH:19]=C(C(Br)=CN=1)C(OC)=O.N(C(CC)C)=C=O.N>>[Br:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH:15]([CH2:18][CH3:19])[CH3:16])=[O:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Agent: CCC(C)N=C=O
Agent: N
Product: CCC(C)NC(=O)Nc1cc(C(N)=O)c(Br)cn1

Procedure:
The compound was synthesized by a method analogous to the synthesis of Intermediate 43 starting with methyl 2-amino-5-bromoisonicotinate, 2-isocyanatobutane and ammonia solution (7N, MeOH). MS (ESP): 303 (M+1) for C10H13BrN4O2
Reaction SMILES: [OH:1][C:2]1C=CC(O)=C[C:3]=1[OH:9].[C:10](OCC)([O:15]CC)([O:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:13]([O:12][C:10]1([CH3:11])[O:9][CH2:3][CH:2]([OH:1])[O:15]1)[CH3:14]
Reactant: CCOC(C)(OCC)OCC
Reactant: Oc1ccc(O)c(O)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC1(C)OCC(O)O1
Yield: 114.1 %

Procedure:
A solution composed of 5.0 g of 1,2,4-trihydroxybenzene, 9.7 g of triethyl orthoacetate and 50 ml of toluene-carbon tetrachloride (1:1) was refluxed for 1.5 hours. The solvent was evaporated, and the residue was purified by column chromatography to give 6.7 g (yield 86%) of the desired product as pale brown crystals having a melting point of 86° to 87° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.Br>C(#N)C>[Br-:10].[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:4]1)([OH:18])=[O:17]
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C(O)CCCCCBr
Reactant: BrCc1cccc2ccccc12
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCCn1c[n+](Cc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 6-bromohexanoic acid (1.44 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)=[C:19]([Cl:33])[CH:18]=1)(=[O:3])[NH2:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:37][CH:34]1[CH2:36][CH2:35]1)=[O:25])[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(N)=O
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (described in WO02/32872; 17.5 g, 37.7 mmol) dissolved in N,N-dimethylformamide (350 mL), was added cyclopropylamine (6.53 mL, 94.25 mmol) under nitrogen atmosphere, and the mixture were stirred at room temperature overnight. The mixture was poured into water (1.75 L), and stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 minutes. Ethanol (300 mL) was added to the crude crystals, the mixture was heated to reflux for about 30 minutes to dissolve the crystals, and gradually cooled to room temperature overnight while stirring. Precipitated crystals were filtered off, dried in vacuo, and dried at 70° C. for 8 hours to give crystals of the title compound (12.91 g, yield 80.2 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[C:11]([OH:15])(=O)[CH2:12]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:9])[C:12]([CH2:11][OH:15])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CO
Reactant: CNc1ccc(Cl)cc1N
Product: Cn1c(CO)nc2cc(Cl)ccc21
Temperature: 150 °C
Yield: 45 %

Procedure:
4-chloro-N1-methylbenzene-1,2-diamine (15.0 g, 96 mmol) and glycolic acid (8.1 g, 106 mmol) were mixed together in a sealed tube. The mixture was heated at 150° C. for 5 hours before it was cooled down to room temperature. The residue was purified by flash column chromatography (0-5% MeOH in CH2Cl2) to give the product (8.5 g, 45% yield). 1H NMR (300 MHz, CDCl3) δ: 3.80 (s, 3H), 4.86 (s, 2H), 7.13-7.22 (m, 2H), 7.62-7.64 (m, 1H).
Reaction SMILES: CC(O)(C#C)C.[CH3:7][C:8]([OH:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])C#C.[OH-].[K+]>>[CH3:26][CH:14]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:12][CH2:11][C:8](=[O:27])[CH3:7]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C#CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
A 100 ml-four-necked flask equipped with a thermometer, a reflux condenser, and a stirrer was charged with 8.61 g (102) mmol 2-methyl-3-butin-2-ol (MBI) and 30.14 g (102 mmol) 3,7,11,15-tetramethyl-1-hexadecin-3-ol (DIP) stirred with 750 rpm and heated up to reflux temperature. After 5 min an internal temperature of 95° C. was reached, and 2 ml KOH (41.42% in H2O, 20.53 mmol) were added. The reaction was controlled by GC (samples were taken after 60 min, 155 min and 385 min). The ketones were separated by distillation. Yield acetone 5.8 g, (97.5%), yield 6,10,14-trimethyl-2-pentadecanon (C18—K) 26.1 g, (96.1%), not optimized.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[OH:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[OH:26])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.