Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[NH2:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=1[C:33]1[CH:41]=[CH:40][C:36]2[O:37][CH2:38][O:39][C:35]=2[CH:34]=1>N1C=CC=CC=1>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:24]3[C:25]([O:29][CH2:30][CH2:31][OH:32])=[N:26][N:27]([CH3:28])[C:23]=3[NH:22][S:9](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:11])=[O:10])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1N
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)/C=C/c1ccccc1
Reaction time: 24 h
Yield: 80.3 %

Procedure:
(E)-2-phenylethensulfonyl chloride (381 mg) and dimethylaminopyridine (77 mg) were added at room temperature under an atmosphere of nitrogen to a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-1-ethanol (200 mg) (Preparation 45) in anhydrous pyridine (6 ml). After 24 h, the mixture was concentrated under reduced pressure. To the yellow solid was added water (30 ml), an aqueous solution of HCl (1N) to acidify the solution and the mixture was extracted with dichloromethane (3×30 ml). The organic fractions were combined, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (6 ml) and dichloromethane (1 ml) and an excess of an aqueous solution of sodium hydroxyde (2N) was added. The reaction was stirred overnight. The reaction mixture was then diluted with dichloromethane (100 ml), acidified with an aqueous solution of HCl (1N). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic fractions were dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:methanol (95:5) to yield the title compound as colourless solid (257 mg).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]1(C(C(C2C=CC=CC=2)O)=O)C=CC=C[CH:13]=1>>[C:5]1([O:6][CH3:7])[C:8](=[CH:10][CH:11]=[C:3]([CH:4]=1)[CH2:2][CH:12]=[CH2:13])[OH:9].[C:5]1([O:6][CH3:7])[C:8](=[CH:10][CH:11]=[CH:3][CH:4]=1)[OH:9]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: COc1cc(C=O)ccc1O
Product: C=CCc1ccc(O)c(OC)c1
Product: COc1ccccc1O

Procedure:
Vanillin has the chemical name 4-hydroxy-3-methoxybenzaldehyde and the chemical structure: ##STR1## Vanillin occurs naturally in vanilla beans, potato parings, and Siam benzoin, and is produced synthetically from eugenol or guaiacol or from the lignin waste from the wood pulp industry.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:7]1[C:8](=[O:29])[O:9][C:10]2[C:20]([CH3:21])=[C:19]([O:22]C3CCCCO3)[CH:18]=[CH:17][C:11]=2[C:12]=1[O:13][CH2:14][CH:15]=[CH2:16])[CH3:6].O1CCCC1>CCCCCC.C(OCC)(=O)C>[OH:22][C:19]1[CH:18]=[CH:17][C:11]2[C:12]([O:13][CH2:14][CH:15]=[CH2:16])=[C:7]([C:5](=[N:4][O:3][CH3:2])[CH3:6])[C:8](=[O:29])[O:9][C:10]=2[C:20]=1[CH3:21]
Reactant: C=CCOc1c(C(C)=NOC)c(=O)oc2c(C)c(OC3CCCCO3)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOc1c(C(C)=NOC)c(=O)oc2c(C)c(O)ccc12
Reaction time: 7 h

Procedure:
10 ml of a 1M aqueous solution of hydrochloric acid is added to a solution containing 1 g of the product prepared in Stage C and 20 ml of tetrahydrofuran. Agitation is carried out for 7 hours at ambient temperature followed by dilution with 50 ml of a hexane-ethyl acetate mixture (1-1). The phases are separated and the aqueous phase is extracted with a hexane-ethyl acetate mixture (1-1). The organic phases are combined and washed with a 1M solution of sodium dihydrogen phosphate, followed by drying, filtering and concentrating to dryness. The residue is triturated with a hexane-ethyl acetate mixture (4-1). After separating and drying 770 mg of product is collected.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])=O.[NH4+:21].[ClH:22]>O>[ClH:22].[CH3:16][CH:15]([NH2:21])[C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Agent: O=C[O-]
Solvent: O
Product: CC(N)c1ccc(CCc2ccccc2)cc1
Yield: 73 %

Procedure:
A mixture of 87.5 g (0.39 mole) of 4'-phenethylacetophenone, M.P. 67°-70° C., prepared according to R. E. Lutz et al., J. Org. Chem. 12, 617 (1947), and 98.5 g (1.56 mole) of ammonium formate is slowly heated to 150° C. with stirring. After the initial foaming has subsided the temperature of the heating bath is raised to 185°-190° C. for a period of 4 hours. Upon cooling, the mixture is treated with several portions of water. To the residue is added 75 ml of concentrated HCl. The mixture is refluxed for 2 hours and is allowed to cool. The resulting solid is collected, washed with several portions of benzene and is recrystallized from isopropanol containing about 5% of water to yield 74.0 g (73% yield) of the desired product, M.P. 212°-214° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]([O:19][C:20](=[O:34])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](=[O:33])N(OC)C)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].O>C1COCC1>[C:15]([O:19][C:20](=[O:34])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([C:28]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:33])[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: c1ccc2scnc2c1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)c2nc3ccccc3s2)CC1
Yield: 82.1 %

Procedure:
To a solution of benzothiazole (675 mg, 0.55 ml, 5 mmol) in THF (20 ml) at −78° C. was added dropwise n-BuLi (2.5M in Hex, 2 ml) such that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before dropwise addition of a solution of [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (716 mg, 2.5 mmol, prepared according to WO 03/053933) in THF (2 ml). The temperature was kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). Mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine and dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography over SiO2 (Hex/EtOAc 4:1 then DCM). The relevant fractions were pooled, evaporated under reduced pressure, digested with Hex and filtered to give 740 mg (82%) of [4-(benzothiazole-2-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[S:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][N:9]=1.Br[CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19]>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:7]1[S:6][C:5]([NH:4][C:1](=[S:3])[S:2][CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19])=[N:9][N:8]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: FC(F)=C(F)CCBr
Reactant: S=C=S
Solvent: CS(C)=O
Product: FC(F)=C(F)CCSC(=S)Nc1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
Carbon disulfide (5.78 grams, 0.076 mole) was added to a stirred solution of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (12.0 grams, 0.071 mole) in dimethyl sulfoxide (36 ml) under a nitrogen atmosphere. The reaction mixture was stirred for three hours at ambient temperature, then cooled to 0° C. at which time 4-bromo-1,1,2-trifluoro-1-butene (16.8 grams, 0.088 mole) was added dropwise. The reaction mixture was stirred at ambient temperature overnight. Crystals that had formed were collected by filtration, washed successively with petroleum ether and hexane and then dried, yielding 8.39 grams of (3,4,4-trifluoro-3-butenyl) N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-dithiocarbamate as a yellow powder. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[S:18][C:12]=3[C:11]2=[O:26])=[CH:6][C:5]=1[O:27][CH3:28].[OH-].[Na+]>CO.O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[S:18][C:12]3[C:11](=[O:26])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([O:27][CH3:28])[CH:6]=4)[CH2:15][CH2:14][C:13]=3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1C(=O)O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
Suspend 4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-benzoic acid methyl ester (0.4 g, 0.94 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) and add 1 N NaOH (1.13 mL, 1.13 mmol). Heat the mixture at reflux for 16 h, cool to RT, and concentrate in vacuo. Suspend the residue in water (25 mL) and acidify with 10% sodium bisulfate. Extract the mixture with ethyl acetate (4×20 mL) to give a suspension in the organic portion. Filter the solid and dry in vacuo to give 0.19 g (49%) of the title compound. Concentrate the filtrate in vacuo to give 0.09 g (23%) more of the title compound. MS/ES m/z (35Cl) 414.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1ccc(I)nc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(-c2ccccc2)nc1Br
Temperature: 70 °C

Procedure:
To a degassed solution of 2-bromo-3-chloro-6-iodopyridine (350 mg, 1.099 mmol) and phenylboronic acid (134 mg, 1.099 mmol), saturated potassium carbonate solution (5.50 mL, 5.50 mmol) in acetonitrile (5 mL) was added tetrakistriphenylphosphine palladium (63.5 mg, 0.055 mmol) and the mixture heated at 70° C. for 2 hours. The mixture was cooled and filtered through diatomaceous earth. The filtrate was concentrated and the residue washed with diethyl ether to afford the crude title compound. LCMS: 267 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.CSC.Cl[Si](C)(C)C.[O:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:26]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:28]([CH3:30])([CH3:29])[CH2:27][C:25](=[O:24])[CH3:26])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: CC(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(F)cc1C(C)(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-4-fluoro anisole (3.24 mL, 25 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under argon was added n-butyl lithium (17.2 mL of 1.6 M solution in hexanes, 27.5 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with a solution of cuprous iodide in dimethyl sulfide (4.76 g in 15 mL, 25 mmol) and stirred for 15 minutes at −78° C. Then chlorotrimethylsilane (6.4 mL, 50 mmol) was added, followed by a solution of mesityl oxide (2.9 mL, 25 mmol) in anhydrous THF (5 mL). The reaction was stirred at −78° C. to −60° C. for 4 hours and then quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (85% yield) which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17](F)[C:18]=3[CH2:20][OH:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH:2][CH3:1])[C:18]=3[CH2:20][OH:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(CO)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1CO
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 1(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-hydroxymethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred overnight at 40° C. The solvent and the like were distilled off, and diethyl ether was added to the residue. A supernatant liquid was removed, and ethanol was added to the resultant residue. Solids deposited were collected by filtration to obtain the title compound (34 mg) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH2:24][OH:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:26])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[C:28]1[CH:29]=[CH:30][C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>>[OH:25][CH2:24][CH2:23][C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:26])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][C:31](=[O:35])[N:32]([CH3:34])[CH:33]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 18 using 5-bromo-1-methylpyridin-2(1H)-one in Step 2. LC-MS Method 2 tR=1.627 min, m/z=447.1; 1H NMR (CDCl3) 1.06 (m, 3H), 1.87-2.06 (m, 2H), 2.11-2.28 (m, 2H), 2.33 (m, 3H), 2.96 (m, 1H), 3.53 (m, 1H), 3.62 (s, 3H), 3.78 (m, 1H), 5.48 (m, 1H), 6.69 (m, 1H), 7.03 (m, 2H), 7.14 (m, 2H), 7.21-7.38 (m, 4H), 7.41 (s, 1H), 7.56 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:26]([O:41][C@H:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:43][C:44](O)=[O:45])(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)CCl>[C:26]([O:41][C@H:42]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:43][C:44]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:45])(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC(C)(C)[Si](OCCCCCCN)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NCCCCCCO
Yield: 30.5 %

Procedure:
In the same manner as described in Example 20-(1), 6-amino-1-(t-butyldiphenylsilyloxy)hexane (1.48 g, 4.15 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (2.07 g, 4.56 mmol) in the presence of EDC.MeI (1.35 g, 4.56 mmol) and then deprotected with TBAF (1.0 M in THF, 1.53 mL, 1.53 mmol) in THF (46 mL) to afford 700 mg (30%) of 6-[(R)-3-tetradecanoyloxytetradecanoylamino]-1-hexanol as an off-white solid.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].CO[C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11](OC)[C:12]=1[O:13][CH3:14].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[N:34]#[C:35][NH2:36]>O.[N+]([O-])(O)=O>[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])=[CH:8][CH:7]=1.[CH3:21][N:22]([CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:35]([NH2:36])=[NH2+:34])=[CH:28][CH:27]=1)[CH3:33]
Reactant: N#CN
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CN(C)CCOc1ccc(NC(N)=[NH2+])cc1

Procedure:
4-(2-Dimethylaminoethoxy)phenylguanidinium dinitrate was prepared by the method described for 3,4,5-trimethoxyphenylguanidinium nitrate in Example 1 from 4-(2-dimethylaminoethoxy)aniline (5.0 g, 28 mmol), cyanamide (1.75 g, 41 mmol) in water (3.5 ml) and concentrated nitric acid (4 ml) to give the product as a light purple solid (6.8 g) m.p. 149-152°. MS (ES+) 223 (MH+, 100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: BrCCBr
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 64.2 %

Procedure:
1,2-Dibromoethane (19.2 ml, 286 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (6.0 g, 22 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (14.4 g, 107 mmol) in DMF. The mixture was stirred at 85° C. for 2.5 hours, allowed to cool and insoluble material was removed by filtration. The solvent was removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (93/7). The product was trituated with ethyl acetate to give 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (5.3 g, 63%). A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (2.0 g, 5.3 mmol) in thiomorpholine (15 ml) was stirred at ambient temperature for 5 hours. The mixture was diluted with water and the resulting precipitate collected by filtration. The solid product was dissolved in methylene chloride, washed with brine and passed through phase separating paper. The solvent was removed by evaporation to give 6-methoxy-4-phenoxy-7-(2-thiomorpholinoethoxy)quinazoline (2.0 g, 94%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCOCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The product from Step B was reacted with sodium hydride (0.220 g, 60% dispersion in oil, 5.4 mmol) and n-propyl iodide (0.375 mL, 3.85 mmol) according to the procedure described in Example 7, Step C. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a foam, (0.400 g).
Reaction SMILES: O[CH:2]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][CH3:4]>C(OCC)(=O)C.CCCCCC>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[C:9]3[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]([CH3:32])=[C:5]([CH2:2][CH2:3][CH3:4])[C:13]=3[O:12][CH2:11]2)=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 86 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in Examples 30 and 31, the title compound was synthesized in the same manner as in Example 23. Yield: 86%. Melting point: 145-148° C. (ethyl acetate-hexane).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C@@H:11]([CH2:17][N:18]([CH3:40])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:39])[CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[CH2:35][C:36](O)=[O:37])[CH2:10]2.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl.ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C@@H:11]([CH2:17][N:18]([CH3:40])[CH2:19][CH2:20][CH2:21][N:22]1[C:23](=[O:39])[CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[CH2:35][C:36]1=[O:37])[CH2:10]2
Reactant: COc1cc(CC(=O)O)c(CC(=O)NCCCN(C)C[C@H]2Cc3cc(OC)c(OC)cc32)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)C(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Thionyl chloride (1.68 mmol, 1.68 eq) is added to a suspension of {2-[2-({3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}amino)-2-oxo-ethyl]-4,5-dimethoxyphenyl}acetic acid (500 mg, 1 mmol) in a mixture of toluene/dichloro-methane (15 ml, 66/33) at 60° C. After remaining in contact for 3 hours 30 minutes, 0.5 mmol of thionyl chloride dissolved in 5 mL of dichloromethane is added (0.5 eq). After remaining in contact for 1 hour 30 minutes, the reaction mixture is cooled to 25° C. 1N aqueous sodium hydroxide solution (10 mL) and dichloromethane (10 mL) are added to the mixture. The two phases are separated, and the organic phase is subjected to drying over sodium sulphate and is then dried. 0.38 g of a dark red oil is obtained. The product may be purified by flash chromatography on a silica column (eluant: dichloromethane/methanol 95/5).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][N:9]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.O>[CH:24]1([C:21]2[CH:22]=[CH:23][C:15]([NH:14][C:11]3[CH:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:27]4[CH2:29][CH2:28]4)=[N:13][CH:12]=3)=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2C2CC2)nc1
Temperature: 110 °C

Procedure:
In a schlenck tube, a mixture of 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid (0.55 mmol, 0.200 g), cyclopropylboronic acid (0.71 mmol, 0.061 g), K3PO4 (1.86 mmol, 0.395 g), PCy3 (0.05 mmol, 0.015 g) and Pd(AcO)2 (0.03 mmol, 0.006 g) in a mixture of toluene/water 6:1 (6 ml) was heated at 110° C. for 72 hours, under argon atmosphere. The crude mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and the solvent removed. The crude mixture was purified by reverse phase chromatography eluting with a gradient of 100% water to 100% MeOH/AcN 1:1 affording 0.016 g (71% of yield).