Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10](B(O)O)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[C:17]([F:28])[CH:16]=1>>[F:28][C:17]1[CH:16]=[C:15]([C:10]2[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:20]=[CH:19][C:18]=1[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(C)Oc1ncccc1B(O)O
Product: CC(C)Oc1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-isopropoxypyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 1H), 8.18-8.13 (m, 1H), 8.12 (d, J=1.4, 1H), 7.99-7.90 (m, 1H), 7.69-7.62 (m, 1H), 7.58-7.41 (m, 2H), 6.98-6.91 (m, 1H), 5.49-5.35 (m, 1H), 4.68 (s, 2H), 1.37 (d, J=6.2, 6H).
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH2:5][CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([O:7][CH2:6][CH2:5][NH:2][NH2:3])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OCCBr
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OCCNN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of hydrazine monohydrate (36.0 mL, 0.750 mol) in ethanol (70 mL) at 0° C. in an ice-water bath was added 2-(2-bromoethoxy)-2-methylpropane (12.1 mL, 0.075 mol) drop-wise over 20 minutes. The reaction was then allowed to warm to room temperature and stir for 5 minutes and then heated to 40° C. in a preheated oil bath for 4 hours. The reaction was then cooled to room temperature and concentrated to remove the ethanol. To the flask was added water (20 mL) and the aqueous layer was extracted with diethyl ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to provide (2-tert-butoxyethyl)-hydrazine as a colorless oil (6.05 g, 61%).
Reaction SMILES: [C:1]([C:7]([O:9]C)=O)#[C:2][C:3]([O:5][CH3:6])=[O:4].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>CO>[CH3:6][O:5][C:3]([C:2]1[NH:16][C:15]2[C:17]([C:7](=[O:9])[CH:1]=1)=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)c1cc(=O)c2cc(Cl)ccc2[nH]1
Temperature: 240 °C
Reaction time: 4 h

Procedure:
Dimethyl acetylenedicarboxylate (13.5 mL) was added to a solution of 4-chloroaniline (12.76 g) in methanol (150 mL), and the thus-obtained mixture was heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in diphenyl ether (70 mL), followed by stirring at 240° C. for 4 hours. After the reaction mixture was cooled, a solvent mixture of hexane and diethyl ether was added thereto. The precipitated crystals were collected by filtration, and were washed, to thereby give the title compound (11.09 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](O)=[O:15])[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:32][NH2:33])=[N:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:32][NH:33][C:14]([C:12]2[C:11]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:10][N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=2)=[O:15])=[N:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cc(C(=O)O)c(N3CCCC3)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)ncc2N2CCCC2)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxylic acid (2-2, 0.026 g, 0.085 mmol) and 1-(5,6-dimethoxy-2-pyridinyl)methanamine (3-6, 0.017 g, 0.102 mmol) in DMF (0.17 mL) was added HATU (0.032 g, 0.085 mmol) followed by DEA (0.074 mL, 0.426 mmol) and stirred at ambient temperature for 1 h. The system was partitioned between saturated aqueous sodium bicarbonate and EtOAc, washed with brine and dried over magnesium sulfate. Filtration and concentration followed by purification via normal phase chromatography (0→10% MeOH in EtOAc) afforded the title compound (2-3) as a salmon powder. 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.40 (m, 1H), 8.32 (s, 1H), 8.06 (m, 1H), 7.08 (s, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 4.63 (d, 2H, J=4.5 Hz), 4.00 (s, 3H), 3.89 (s, 3H), 3.36 (m, 4H), 2.40 (s, 3H), 1.93 (m, 4H). HRMS[M+H]C24H22N5O3 calc'd 434.2187. found 434.2211.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([O:35][C:31]5[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=5)[CH:41]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Oc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-bromo-3-phenoxy-benzene.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+]>[C:15]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC(Cc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 25 ml of 0.1N NaOH, was dissolved 2 g of 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid. To the resulting solution, 3.8 ml of benzoyl chloride was added dropwise. The reaction mixture was maintained at a temperature of 0° C. for the duration of the reaction. The pH was maintained in a range of approximately by the addition of 0.2N NaOH. After about 3 hours, the reaction mixture was acidified with concentrated hydrochloric acid. The precipitate was removed by filtration and taken up in boiling carbon tetrachloride. The precipitate was then crystallized to yield a 2-(benzoylamino)-3-(3,4-dibenzoyloxyphenyl)propanoic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH:26]O>C(O)(=O)C>[ClH:2].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5](=[O:26])[C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OO
Reactant: CN(C)CCN1C(=O)C(Cl)=C(c2ccccc2)Sc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCN1C(=O)C(Cl)=C(c2ccccc2)S(=O)c2ccccc21
Reaction time: 16 h

Procedure:
3-Chloro-5-[2-(dimethylamino)ethyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one, hydrochloride (prepared as described in Example 1) is treated with one equivalent of hydrogen peroxide in dilute acetic acid, and allowed to stand for about 16 hours. Solvent removal yields the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]([C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:15])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][C@H:18]2[CH2:17][OH:16])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])#[N:9]
Reactant: COc1ccc(C(=O)CBr)c(C)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(bromoacetyl)-6-methoxy-2-methylbenzonitrile (2.25 g, 8.40 mmol) in THF was added tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.18 g, 10.8 mmol) and Hunig's Base (2.93 mL, 16.8 mmol). The reaction was allowed to stir at RT for 16 hours. TLC showed good reaction at that point. The crude reaction was adsorbed onto silica gel, and purified by silica gel flash chromatography to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[N:3]1[CH2:33][C:34]([F:37])([F:36])[F:35]>C(O)(C(F)(F)F)=O>[NH2:23][CH2:22][C:21]1[CH:31]=[CH:32][C:18]([C:9]2[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]3[N:3]([CH2:33][C:34]([F:37])([F:35])[F:36])[C:2](=[O:1])[CH2:7][O:6][C:5]=3[N:8]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC(F)(F)F)C(=O)CO3)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC(F)(F)F)C(=O)CO3)cc1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(2-oxo-7-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (45 mg, 0.088 mmol) was dissolved in TFA (1 mL). The resulting mixture was stirred for 30 seconds at room temperature and evaporated under reduced pressure. The deprotected compound was taken back twice into diethyl ether and the solid formed was washed twice with diethylether. The remaining solvent was removed under reduced pressure and dried to afford the title compound (34 mg, 94%) as off-white solid. LCMS (Method D): RT=0.82 min, M+H+=414. 1H NMR (500 MHz, CDCl3): 8.25 (2H, br), 7.47 (1H, s), 7.28-7.26 (4H, m), 7.20-7.18 (3H,m), 7.10-7.08 (2H, m), 4.88 (2H, s), 4.64-4.59 (2H, q), 3.92 (2H, s).
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](Cl)=[CH:10][C:9]([CH3:17])=[N:8]3)[N:5]=[C:4]([CH3:18])[CH:3]=1.C([Mg]Br)C[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:17][C:9]1[CH:10]=[C:11]([CH2:15][CH2:2][CH2:3][CH3:4])[C:12]2[C:7](=[C:6]3[C:15](=[CH:14][CH:13]=2)[C:2]([CH2:24][CH2:23][CH2:22][CH3:21])=[CH:3][C:4]([CH3:18])=[N:5]3)[N:8]=1
Reactant: Cc1cc(Cl)c2ccc3c(Cl)cc(C)nc3c2n1
Reactant: CCCCCC[Mg]Br
Product: CCCCc1cc(C)nc2c1ccc1c(CCCC)cc(C)nc12

Procedure:
4,7-dichloro-2,9-dimethyl-1,10-phenanthroline, Phen1, is synthesized according to the literature (M. Schmittel, H. Ammon Eur. J. Org. Chem. 1998, 785.). For the substitution with a n-butyl group, an equimolar amount of n-HexMgBr and CuBr is added. The purification of Phen2 is done using column chromatography over silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([Cl:32])[CH:23]=1.CO.[OH-].[K+]>>[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:27])=[C:24]([Cl:32])[CH:23]=1
Reactant: COc1cc(C=O)c(Cl)cc1OCc1nc2ccccc2[nH]1
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (4, 783.9 mg, 0.005138 mol, prepared as described in Example 4) and 4-(H-benzoimidazol-2-ylmethoxy)-2-chloro-5-methoxy-benzaldehyde (137, 1.79 g, 0.00565 mmol) were combined in methanol (100 mL, 2 mol) and potassium hydroxide (2.88 g, 0.0514 mol) was added. The reaction was stirred at room temperature overnight. The reaction was adsorbed onto silica and purified by silica gel column chromatography, eluting with 1-15% methanol:dichloromethane to provide the desired compound as a yellow oil, which was redissolved in 200 mL of 25% ethyl acetate:hexanes and concentrated to provide a yellow solid (138, 1.2 g, 50%). MS (ESI) [M+H+]+=469.1, 471.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[N:49][CH:50]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1.Cl>CCO>[Cl:22][C:13]1[CH:12]=[C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[F:1])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Cc1ccc(N)c(F)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C)cc1F
Yield: 44 %

Procedure:
2-Fluoro-4-methylaniline and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, to give ethyl 6-chloro-4-(2-fluoro-4-methylanilino)nicotinate (44%); m.p. (EtOH/water) 107-109° C. 1H NMR [400 MHz, CDCl3] δ 9.63 (br s, 1H), 8.77 (s, 1H), 7.20 (t, J=8.2 Hz, 1H), 7.05-6.99 (m, 2H), 6.65 (d, J=1.6 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (FAB+) 309 (40%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH:9]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:8]2>Br>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH:9]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:8]2
Reactant: CCCN(CCC)C1CNc2c(cccc2OC)C1
Agent: Br
Product: CCCN(CCC)C1CNc2c(O)cccc2C1
Yield: 94.9 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methoxy-N,N-dipropyl-3-quinolinamine (0.98 g) in hydrobromic acid (20 mL of 48%) was heated at 155° C. for 6 hours. The solution was cooled, evaporated, and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was re-extracted with ethyl acetate and the combined organic phases were evaporated to give 0.88 g of 1,2,3,4-tetrahydro-8-hydroxy-N,N-dipropyl-3-quinolinamine as an oil.
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH:16][CH3:15])=[S:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN)c[nH]1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCCCc1c[nH]c(NC(=N)N)n1
Reaction time: 8 h

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)imidazole (0.15 g.) and methylisothiocyanate (0.1 g.) in ethanol (10 ml.) was stirred overnight and then evaporated to dryness. The residue was purified by chromatography on a silica gel column using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.3 v/v/v. The appropriate fractions on evaporation gave a gum which crystallized on triturating in petroleum ether (b.p. 40°-60° C.) to give 2-guanidino-4-[4-(3-methylthioureido)butyl]imidazole, m.p. 179°-184° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].N1CCCCC1>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18]2/[C:16](=[O:17])[NH:15][C:13](=[S:14])[S:12]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1ccc(/C=C2\SC(=S)NC2=O)cc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
4-Ethoxybenzaldehyde (2.78 mL, 20.00 mmol) and rhodanine 7 (3.75 g, 32.0 mmol) were dissolved in 80 mL of anhydrous ethanol at room temperature, and piperidine (0.60 mL, 6.0 mmol) was added to the reaction flask. The reaction mixture was stirred at 75° C. for 1 day and then allowed to cool down to room temperature until a yellow crystalline precipitate formed, and the solid was collected by filtration, washed with water and ethyl acetate, and dried to afford compound 8 in 80.0% (2.99 g) yield as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:12][CH2:13][Mg+].[Br-].[Cl-].[NH4+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[CH2:12][CH3:13]
Reactant: CC[Mg+]
Reactant: COc1cc(C)ccc1C=O
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)c1ccc(C)cc1OC
Reaction time: 2 h

Procedure:
To a stirring solution of 2-methoxy-4-methylbenzaldehyde (1 g, 6.66 mmol) in diethyl ether (35 ml) at 0° C. is added EtMgBr (2.220 ml, 6.66 mmol). The mixture is stirred for 2 hours and then added to sat ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined organic portions are washed with NaHCO3, water and brine dried (MgSO4) and reducing under vacuum to yield the title product as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 1H), 6.78 (d, 1H), 6.72 (s, 1H), 4.77 (t, 1H), 3.85 (s, 3H), 2.37 (s, 3H), 1.83 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:21])([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[C:9]([F:12])([F:11])[F:10].O>C(OCC)C>[F:7][C:8]([F:21])([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1)[C:9]([F:10])([F:12])[F:11]
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
0.79 g of lithium aluminum hydride was suspended in 50 ml of diethyl ether, and a solution of 4.6 g of 4-pentafluoroethylbenzonitrile in 30 ml of diethyl ether was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes, and 5 ml of water was added dropwise over 30 minutes. The insoluble matter was removed by filtration. The ether layer was dried, and then diethyl ether was evaporated under reduced pressure to give 4.7 g of the desired 4-pentafluoroethylbenzylamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][Cl:17])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:19](N)=[NH:20]>C(O)C>[Cl:17][CH2:16][CH2:15][O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:19][N:20]=[C:4]2[OH:5]
Reactant: COC(=O)c1cc(OCCCl)c(OC)cc1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: COc1cc2ncnc(O)c2cc1OCCCl
Temperature: 130 °C
Yield: 86 %

Procedure:
To a solution of methyl 2-amino-5-(2-chloroethoxy)-4-methoxybenzoate (3.61 g, 13.9 mmol) in ethanol was added formamidine hydrochloride and the mixture heated in a sealed tube at 130° C. overnight. The reaction was cooled to room temperature and filtered to give 6-(2-chloroethoxy)-4-hydroxy-7-methoxyquinazoline (3.05 g, 12.0 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 12.09 (br s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7.16 (s, 1H), 4.36 (t, 2H), 4.00 (t, 2H), 3.92 (s, 3H); LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:30][C@H:31]1[O:33][CH2:32]1)(=O)=O>>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[CH:7]2)[C@H:31]1[O:33][CH2:32]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C(C1=Cc2cccc(O)c2OC1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(C1=Cc2cccc(OC[C@@H]3CO3)c2OC1)N1CCOCC1
Yield: 77.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 4-(8-hydroxy-2H-chromen-3-ylcarbonyl)morpholine (3.3 g), potassium carbonate (3.5 g) and (S)-glycidyl nosylate (3.3 g), the title compound (3.1 g) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:12]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)cccc1OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(OCc2ccccc2)c1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 46.6 %

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzaldehyde (200 mg) in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (303 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, and diethyl ether was added. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[F:15][C:16]1([F:34])[CH2:21][CH2:20][C:19]([CH2:32][NH2:33])([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[F:34][C:16]1([F:15])[CH2:17][CH2:18][C:19]([CH2:32][NH:33][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=[CH:5][C:6]=2[CH3:12])([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Product: Cc1ccc(C(F)(F)F)cc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 5-trifluoromethyl-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=481.1, tR (minutes, Method D)=0.86
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][OH:17])[CH2:12][N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:9]=2[CH:28]=1>CCOCC.O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][O:17][CH3:3])[CH2:12][N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:9]=2[CH:28]=1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of diazomethane in ether was added to a suspension of 6 g (0.0163 mole) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine in 100 ml of tetrahydrofuran. After sitting at room temperature for 1 hr the excess diazomethane was destroyed by addition of glacial acetic acid. The solvent was evaporated under reduced pressure and the residue was passed over 100 g of silica gel using methylene chloride. Crystallization from ether/hexane gave light yellow crystals with mp 130°-133° C.