Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:32])([O:30][CH3:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:30][CH3:31])([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: COP(=O)(Cl)OCc1ccccc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Product: COP(=O)(OCc1ccccc1)OCN1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-Dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one and benzyl methyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7](=[O:14])[O:8][C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]=2[CH:4]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CCOCC>[NH2:2][C:3]1[CH:16]=[C:15]([CH3:17])[C:6]2[C:7](=[O:14])[O:8][C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1nc2cc(N)ccc2c(=O)o1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CCOc1nc2cc(N)cc(C)c2c(=O)o1

Procedure:
1.0 g of 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one HCl suspended in 50 ml of ether is stirred with a twofold stoichiometric excess of dilute aqueous potassium carbonate solution until the salt is completely dissolved. The organic layer is then separated, washed twice with water, dried over magnesium sulfate and evaporated to yield 7-amino-2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one as the free base.
Reaction SMILES: C(O[C:4]([CH:6](NC1C=CC=CC=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])O)=O)C.S(=O)(=O)(O)O.C([O:31][C:32](=O)[NH:33][C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1)C>>[CH:11]1[CH:12]=[C:7]([CH2:6][C:4]2[CH:38]=[CH:39][C:34]([N:33]=[C:32]=[O:31])=[CH:35][CH:36]=2)[C:8]([N:13]=[C:14]=[O:16])=[CH:9][CH:10]=1
Reactant: CCOC(=O)Nc1ccccc1
Reactant: CCOC(=O)C(Nc1ccccc1)c1ccccc1NC(=O)O
Agent: O=S(=O)(O)O
Product: O=C=Nc1ccc(Cc2ccccc2N=C=O)cc1
Temperature: 100 °C

Procedure:
0.3 g. of an ethyl ester of 2-[(ethoxycarbonyl)-phenylaminomethyl]phenylcarbamic acid (N-benzyl compound), prepared as in Example 1, along with 1.0 g. of 96.4 weight percent concentrated sulfuric acid was charged to a 300 ml reaction flask. The mixture was heated to 100° C. on a constant temperature bath for 60 minutes. High speed liquid chromatographic analysis showed conversion of the ethyl ester of 2-[(ethoxycarbonyl)phenylaminomethyl]phenylcarbamic acid to the diethyl ester of 2,4'-methylenebis(phenylcarbamic) acid and higher homologs to be 99+ percent with minor amounts of ethylphenylcarbamate. After acid extraction with water, the resulting 2,4'-methylenebis(phenylcarbamic) acid, diethyl ester (diurethane) was subjected to thermal decomposition by the method described in U.S. Pat. No. 3,962,302 to produce the diphenylmethane-2,4'-diisocyanate in good yield.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH:12](O)[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>CC#N>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][I:39])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A stirred solution of 133 (0.78 g, 3.8 mmol), PPh3 (1.1 g, 4.3 mmol), imidazole (0.40 g, 5.8 mmol), and CH3CN (20 mL) at 0° C. was treated with iodine (1.0 g, 4.3 mmol). After 15 min the cooling bath was removed and stirring continued for 5 h. The reaction mixture was then diluted with H2O and extracted with hexanes (5×25 mL then 4×50 mL). The combined extracts were dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 134 (0.99 g) as a colorless oil. Rf 0.44 (silica, 20% EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:17][NH:13][C:14]([N:1]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([NH:13][CH3:17])=[O:15])=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cnc2ccccc2c1
Solvent: c1ccncc1
Product: CNC(=O)N(C(=O)NC)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.0 g of 3-aminoquinoline are added in portions to a solution of 1.65 ml of N,N-dimethylcarbamoyl chloride in 3.9 ml of pyridine and the reaction mixture is stirred at room temperature for 24 h. The reaction mixture is then poured onto 50 ml of ice-water. Customary working up and purification of the crude product by chromatography over 100 g of silica gel (mobile phase L) gives 3-(N,N-dimethylaminocarbonylamino)quinoline: Rf (L)=0.23; MS:M+=215.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([CH2:7][CH2:8][CH:9]=O)=O.C([O-])(=O)C.[NH4+:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:19][CH:9]=[CH:8][CH:7]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=CCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Clc1ccc(-c2ccc[nH]2)cc1Cl
Yield: 83.4 %

Procedure:
To a suspension of 3-(3,4-dichlorobenzoyl) propionaldehyde (6 g, 26 mmol) in 60 mL of absolute ethanol is added ammonium acetate (4 g, 52 mmol). The reaction is refluxed for 20 minutes and allowed to cool. Most of the ethanol is rotary evaporated and 200 mL of 1:1 dichloromethane-diethyl ether along with 50 mL of water is added. The layers are separated and the organic phase is dried over sodium sulfate. Rotary evaporation yields a dark brown oil which is chromatographed over silica gel using 3:1 hexane-ethyl acetate as eluent to give the pyrrole (4.6 g, 83%) as a light brown solid, m.p. 49°-51° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:27]2[CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:29]1[CH2:30][CH:27]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:28]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CN(C(=O)C(F)(F)F)C2)ccc2c1OCC1CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CNC2)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 88, 0.294 g) and potassium carbonate (0.155 g) in methanol (5 mL) and water (0.5 mL) was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo and the residue was triturated with 10% methanol in DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-[2-(azetidin-3-yl)-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.216 g) as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][C:12](OC(C)(C)C)=O)[CH:5]=1.CI.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)c1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and MeI (2.2 mL) in DMF (40 mL) was added portionwise at 0° C. NaH (55% dispersion in mineral oil, 1.4 g). Stirring was continued at 0° C. for 15 min and at 20° C. for 30 min. The mixture was partitioned between AcOEt and brine, the pH being set to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residue was stirred in a mixture of CH2Cl2 (30 mL) and TFA (30 mL) for 40 min at 20° C. After the evaporation of the solvents, the solution of the residue in AcOEt was extracted with ice-cold sat. Na2CO3 solution and the aqueous extracts were immediately acidified with 3N HCl and extracted with AcOEt. The solvent of this extract was evaporated and the residue heated in a mixture of toluene (40 mL) and 3N HCl (3 mL) to 100° C. for 1 h. The cooled mixture was diluted with AcOEt, washed with sat. NaHCO3 and brine, dried and evaporated to give 3-propionyl-benzoic acid methyl ester (3.87 g) as white solid, MS (ISP) 193.2 [(M+H)+].
Reaction SMILES: [C:1]1([C:7](=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:31]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:24]=[CH:23][C:22]=3[N:21]=[C:20]2[CH2:32][CH2:33][CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:44])C=1>>[O-:44][N+:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:35])[C:20]([CH2:32][CH2:33][CH3:34])=[N:21][C:22]=2[CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)c1ccccc1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCCCCCCCC(=O)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-phenyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecan-1-one (6.0 g, 12.8 mmol) by reaction with m-CPBA (8.18 g) to provide 12-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenyldodecan-1-one followed by reaction with p-toluenesulfonyl chloride (3.65 g, 19.2 mmol) and ammonium hydroxide solution (40 mL). The product was dissolved a mixture of ethanol and diethyl ether, and a solution of hydrogen chloride (1 equivalent of a 1.0 M solution in diethyl ether) was added. A precipitate formed, and the solvents were removed under reduced pressure. The resulting solid was recrystallized from a mixture of isopropanol and hexane to provide 12-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenyldodecan-1-one hydrochloride as an off-white solid, mp 195-196° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](Cl)=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1.C(N(C(C)C)C(C)C)C>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Temperature: 90 °C

Procedure:
A mixture of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate (48.1 mg, 0.10 mmol, 1.00 equiv), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (20.1 mg, 0.10 mmol, 1.00 equiv), and N-ethyl-N-isopropylpropan-2-amine (25.4 mg, 0.20 mmol, 1.97 equiv) in ethanol (3 ml) was heated overnight at 90° C. in an oil bath. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (1:1) to afford the title compound. as a yellow solid. MS m/z [M+H]+ (ESI): 645.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.Cl>N1C=CC=CC=1>[S:11]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1CCC(CO)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.20 g of the 4-(hydroxymethyl)cyclohexanecarbonitrile obtained in 5 ml of pyridine was treated portionwise with 2.46 g of tosyl chloride at room temperature and while gassing with argon. After stirring at room temperature for 3.5 hours (formation of a white precipitate), the mixture, cooled to 0° C., was treated with about 2 ml of water, cautiously made acid with about 7 ml of concentrated hydrochloric acid and extracted three times with 30 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated, there remaining behind 2.31 g of a semi-crystalline oil. Low-pressure chromatography (0.5 bar) on 480 g of silica gel using 30% ethyl acetate/petroleum ether as the eluant gave 1.06 (42%) of trans-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, crystallizing oil (m.p. 84°-85° C.) and 1.03 g (41%) of cis-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, viscous oil. Rf values (30% ethyl acetate/petroleum ether): trans product 0.25, cis product 0.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.CC[N:14]([CH:18]([CH3:20])[CH3:19])C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:14][CH:18]2[CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To solution of 4-bromo-2-fluoronitrobenzene (2M g, 0.0091 mol) in DMF (10 ml) was added carefully DIPEA (3.25 ml, 0.0182 mol) and cyclopropylamine (0.7 ml, 0.0091 mol) and the resulting solution was stirred at room temperature for 14 h. The reaction was quenched with ice-water and extracted with diethyl ether (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the title compound (5-bromo-2-nitro-phenyl)-cyclopropylamine as a yellow solid. C9H9BrN2O2; 1H NMR (400 MHz, DMSO-d6), δ: 8.08 (brs, 1H), 8.02-7.99 (d, J=8.8 Hz, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 6.82-6.79 (dd, J=8.8 Hz, 1.6 Hz, 1H), 2.58-2.54 (m, 1H), 0.97-0.88 (m, 2H), 0.69-0.65 (m, 2H). MS (M+1): 258.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH3:9].S(=O)(=O)(O)O>O>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:8][CH3:9])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(F)(F)F

Procedure:
in a first stage, trifluoroacetic acid is brought into contact with a slight excess of ethanol in the presence of concentrated sulfuric acid and a solvent, the solvent having a boiling point higher than that of trifluoroacetic acid and specific gravity relative to water less than 1 and which solvent does not form an azeotrope with ethyl trifluoroacetate, and then carrying out a phase separation and removing the sulfuric layer, followed, if required, by an additional stage in which concentrated sulfuric acid is added to complete the esterification;
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41]>C(Cl)Cl>[CH2:40]([NH:42][C:43]([N:21]1[CH2:22][CH2:23][C:17]2[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])=[N:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=3)=[N:19][C:18]=2[CH2:20]1)=[O:44])[CH3:41]
Reactant: CCN=C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)NCC)C3)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 13 as a hydrochloride salt) (99 mg, 0.25 mmol) in DCM (3 mL) at room temperature (20° C.) was added DIPEA (44 uL, 0.26 mmol) followed by ethyl isocyanate (22 uL, 0.27 mmol). The reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford a brown solid (55 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[C:19]([CH3:28])[N:18]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][C:17]1[C:26]2[C:21](=[C:22]([NH:27][C:10]([NH:9][CH2:8][C:6]3[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=3)=[O:11])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2c(C)n1
Temperature: 25 °C

Procedure:
The product from Example 205A (4.4 mmol) in toluene (10 mL) was treated with 1,3-dimethyl-5-isoquinolinamine (375 mg, 2.18 mmol) and DIEA (3.5 mL). The mixture was heated at 80° overnight. After cooling to room temperature, the precipitated solids were collected by filtration and chromatographed on silica gel (98:2 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.13 (d, 1H, J=7.8 Hz), 7.75-7.83 (m, 2H), 7.61 (s, 1H), 7.38-7.51 (m, 3H), 7.18 (t, 1H, J=6.1 Hz), 4.46 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.59 (s, 3H); MS (ESI+) m/z 392 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH3:15][NH2:16]>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:16][CH3:15])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CCO
Product: CNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (18 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, whilst stirring, to 40 ml of a 33% strength solution of methylamine in ethanol. The temperature rises to 50° C. and the expected derivative precipitates immediately. When the addition has ended, the stirring is maintained for 5 minutes and the 2,6-dinitro-4-methyl-N-methylaniline is then filtered off and washed with water; after recrystallisation from alcohol and drying in vacuo, it melts at 132° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](C)(C)[O:20][SiH2]C(C)(C)C)=[C:15]([CH:28]([CH3:30])[CH3:29])[CH:14]=2)=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[C:15]([CH:28]([CH3:29])[CH3:30])[CH:14]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(C)(C)O[SiH2]C(C)(C)C)c(C(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of methyl{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate (Intermediate 154, 288.0 mg, 0.66 mmol) in 5 mL THF at 0° C. was added tetrabutylammonium fluoride (471.0 mg, 1.80 mmols; 1.8 mL of a 1M solution in THF). The pale-yellow solution was stirred for 15 minutes and quenched by the addition of ice cold H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5-10% EtOAc-hexanes) afforded 180.0 mg (85%) of the title compound as a colorless solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3].O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:9])=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1O
Reactant: [N-]=[N+]=NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a suspension of 5-azidovaleric acid (715 mg; 5 mmol; Example 2.2) and N-hydroxysuccinimide (632 mg; 5.5 mmol; Aldrich) in 30 ml dichloromethane, was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g; 5.5 mmol; Aldrich), and the reaction was stirred 12 h at room temperature. To the reaction mixture, was added water (50 ml), and the separated organic phase was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, dried in vacuo. The product was purified via flash chromatography on silica gel (240-400 mesh) in 3:1 (v/v) hexane:ethyl acetate. Yield: 843 mg (3.5 mmol, 70% yield). M+H+: expected, 241.09.7; found, 241.03.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21]1.[OH:31][P:32]([OH:35])([OH:34])=[O:33]>CO.C(O)C>[P:32](=[O:31])([OH:35])([OH:34])[OH:33].[OH:20][CH:22]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:19][CH:18]=2)[CH2:13][CH2:14]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CC(O)COc3ccccc3)CC2)cc1

Procedure:
To a solution of 13.31 g (47 mmol) 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine in 50 mL methanol add 6.4 mL (47 mmol) 1,2-epoxy-3-phenoxypropane. Stir the reaction mixture at roomtemperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride: MeOH, 9:1). When the reaction is complete, remove the solvents in vacuo toobtain an oil. Dissolve the oil in ethanol with one equivalent of H3PO4 and remove the solvents to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([Br:11])=[C:9]([I:12])[CH:8]=[C:7]([Si](C)(C)C)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[C:10]([Br:11])=[C:9]([I:12])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc([Si](C)(C)C)cc(I)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nccc(I)c1Br

Procedure:
A solution of 14.8 g (36 mmol) of 2-tert-butyl-3-bromo-4-iodo-6-trimethylsilylpyridine and 14.0 g (40 mmol) of tetrabutylammonium fluoride trihydrate in 150 ml of THF is heated under reflux for 5 min. After cooling and removal of the THF in vacuo, the residue is taken up in 200 ml of dichloromethane, the org. phase is washed five times with 100 ml of water each time and dried over sodium sulfate. After removal of the dichloromethane in vacuo, the residue is recrystallised from ethanol. Yield: 9.2 g (27 mmol), 75%. Purity: >95% according to 1H-NMR.