Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>Cl>[Cl:13][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: Cl
Product: Clc1nc2ccccc2[nH]1
Yield: 87.9 %

Procedure:
A solution of 2-benzimidazolinone (11.0 g.) and conc. hydrochloric acid (1 drop) in phosphorus oxychloride (126 g.) was stirred for 14 hours at 110° C. After cooling, the mixture was concentrated under reduced pressure to remove excess phosphorus oxychloride. Water was added to the residue and sodium bicarbonate was added thereto to neutralize the mixture. The resulting mixture was extracted four times with ethyl acetate. The combined ethyl acetate extracts were washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystals of 2-chlorobenzimidazole (11.0 g.). To the crystals were added aminoacetaldehyde diethyl acetal (35.5 g.) and dried toluene (80 ml.) and the resulting solution was stirred for 17 hours at 115° C. After cooling, the reaction mixture was extracted by adding a sodium bicarbonate aqueous solution and ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil. The oil was crystallized by adding benzene and hexane to give 2-benzimidazolylaminoacetaldehyde diethyl acetal (11.0 g.), mp 117° to 121° C. The mother liquor was purified by column chromatography on silica gel (100 g.) using a mixture of ethyl acetate and benzene (1:1) to give the same compound (1.5 g.).
Reaction SMILES: [N:1]1C2C(=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20][CH:19]1[C:28](Cl)=[O:29]>>[CH2:2]([NH:1][C:28]([C:19]1[O:18][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH:20]=1)=[O:29])[CH2:3][CH3:4]
Reactant: c1ccc2ncccc2c1
Reactant: O=C(Cl)C1COc2ccccc2O1
Solvent: CCN(CC)CC
Product: CCCNC(=O)C1=COc2ccccc2O1
Yield: 110.4 %

Procedure:
This compound was prepared from the amine of Example 11 (1.90 g, 10.0 mmol), triethylamine (2.77 ml, 20.0 mmol) and 2,3-dihydro-1,4-benzodioxin-2-carbonyl chloride (1.88 g, 9.5 mmol) using the method described in Example 6. The crude gum was purified by chromatography (silica; ether) to give the product (2.30 g, 69%) as an oil which was converted into the thioamide of Example 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:17][CH:18]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: ClCCCOc1c(Cl)cc(-c2csc(-c3ccccc3)n2)cc1Cl
Reactant: c1c[nH]cn1
Product: Clc1cc(-c2csc(-c3ccccc3)n2)cc(Cl)c1OCCCn1ccnc1

Procedure:
The title compound was prepared as described in Example 22 using 4-[3,5-dichloro-4-(chloropropoxy)phenyl]-2-phenylthiazole (4.2 g, 11 mmol) and imidazole (2.2 g, 33 mmol) in place of dibutylamine to give 1.9 g (40% yield) of the free base of the title compound which was converted to the HCl salt, mp 204°-207° C. IR(KBr): 3400, 2540 cm-1, MS: 430(MH+). 1H NMR (CD3OD): δ9.08 (brs, 1H), 8.03-7.48 (m, 10H), 4.65 (t, J=5.0 Hz, 2H), 4.12 (t, J=4.5 Hz, 2H), 2.50 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:20][CH2:21][O:22][CH3:23])[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino) propanoic acid (1 g, 4.48 mmol, Eq: 1.00) was combined with DMF (9 mL) to give a colorless solution. Sodium hydride (394 mg, 9.86 mmol, Eq: 2.2) was added. After 30 min, 1-bromo-2-methoxyethane (747 mg, 505 μL, 5.38 mmol, Eq: 1.2) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) to give (S)-2-[benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-propionic acid (0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)cc3)nc12
Yield: 38.5 %

Procedure:
Reaction of 1-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 4-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (118 mg, 39%). MS (ISP) 306.9 [(M+H)+]; mp 198° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:45]=[CH:44][NH:43][N:42]=1>>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:37])[F:38])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:44]=[CH:45][C:41]([Cl:40])=[N:42]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: Clc1cc[nH]n1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccc(Cl)n2)cc1

Procedure:
The title compound was prepared by the method of Preparation 18a using {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester and 3-chloro-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10](F)=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7].[C:18](=O)([O-])[O-:19].[K+].[K+].Cl>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([O:19][CH3:18])=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(OC)c(F)c1C(=O)O
Reaction time: 3 h
Yield: 83 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser, a stirrer and a dropping funnel, 20 ml of a methanol solution of 10 g (0.0397 mol) of the 3,4,5,6-tetrafluorophtalic acid-monomethyl ester prepared in Example 14 was charged. Then, 8.21 g (0.060 mol) of potassium carbonate was added thereto. The mixture was stirred for 3 hours under reflux. After completion of the reaction, the reaction mixture was neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 8.7 g of 4-methoxy-3,5,6-trifluorophthalic acid-1-methyl ester. (=5-methoxy-3,4,6-trifluorophthalic acid-2-methyl ester.) The yield was 83.1%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24].C(N(CC)CC)C>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CCN1CCCC1CN
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-aminomethyl- 1-ethyl-pyrolidine (882 mg, 6.88 mmol) and triethylamine(1.92 mL, 13.76 mmol) were reacted. The crude product (2.64 g) was carried on to the next step without purification. LC-MS (m/z) 382.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][CH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)=[O:17]
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Reactant: NCc1nnn[nH]1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)NCc3nnn[nH]3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 5-aminomethyltetrazole were reacted together under the conditions described for the preparation of Dye 6 to form Dye 16, m.p. 220°-225° decomp., after crystallization from aqueous acetic acid, λmax (methanol)=350 nm.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Yield: 42.3 %

Procedure:
The title compound (0.16 g, 42%) was prepared by the general method of Example 402 from (7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol), 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 402, 4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:14][CH:13]([CH2:15][OH:16])[CH:12]([OH:17])[C:9]32[CH2:11][CH2:10]3)[C:4](=[O:18])[N:3]=1.Cl[C:20]1[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=1[O:22][P:23](=[N:25][C@@H:26]([CH3:37])[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:24].CN1C=CN=C1>C1COCC1.N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:14][C@H:13]([CH2:15][O:16][C:38]3[CH:39]=[CH:40][CH:41]=[CH:20][C:21]=3[O:22][P:23](=[N:25][C@@H:26]([CH3:37])[C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[O:24])[C@@H:12]([OH:17])[C:9]32[CH2:11][CH2:10]3)[C:4](=[O:18])[N:3]=1
Reactant: C[C@H](N=[P+]([O-])Oc1ccccc1Cl)C(=O)OCc1ccccc1
Reactant: Nc1ccn(C2OC(CO)C(O)C23CC3)c(=O)n1
Agent: Cn1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C2(CC2)[C@@H]1O)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
Compound 1 (100 mg) was dissolved in dry THF/pyridine together with (2S)-benzyl 2-(chloro(phenoxy)phosphorylamino)propanoate (279 mg, 2.0 eq). The mixture was cooled to −78° C. N-methylimidazole (NMI) (259 mg, 8 eq) was added and this mixture was stirred for 15 minutes at −78° C. and then stirred at RT overnight. The resulting mixture was evaporated to dryness. 10 mL CH2Cl2 added and the residue washed with 10 mL 0.5N HCl. The organic layer was separated and washed with 10 mL water, dried on Na2SO4, filtered and evaporated. The compound was purified by silica gel chromatography using CH2Cl2 to CH2Cl2/MeOH 9-1 as the eluent. (Rf=0.2 in this eluent). A yellow solid was obtained, which was repurified using column chromatography using EtOAc to EtOAc/MeOH 8-2 as the eluent. After evaporation and drying overnight in vacuo, 80 mg (33.4%) of 2a was obtained (mixture of diastereomers). LC-MS: Rt: 3.37 min m/z: 569 (M−H)−. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.31-0.41 (m, 1H), 0.43-0.58 (m, 2H), 0.95-1.06 (m, 1H), 1.20-1.31 (m, 3H), 3.82-4.01 (m, 3H), 4.09-4.23 (m, 1H), 4.23-4.36 (m, 1H), 4.98-5.15 (m, 2H), 5.29-5.39 (m, 1H), 5.70 (d, J=7.43 Hz, 1H), 6.07 (s, 1H), 6.13 (dd, J=12.81, 10.47 Hz, 1H), 7.08-7.25 (m, 6H), 7.29-7.39 (m, 6H), 7.54 (d, 1H).
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[I-].[K+].S(=O)(=O)(O)O>CN(P(N(C)C)(N(C)C)=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])=[CH:26][CH:25]=1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (5 g, 0.0138 mole) in 9 ml of HMPT, at 24°, is added p-chloroaniline (5.27 g, 0.0413 mole) and a catalytic amount of potassium iodide (60 mg). The reaction mixture is stirred at 70° for four days. The reaction is then poured into ice-water (30 ml) and 10 ml of 2 N sulfuric acid which is extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×30 ml) and brine (10 ml), dried over calcium sulfate, filtered and evaporated. The crude product is purified by preparative TLC to yield the m-phenoxybenzyl ester of N-(p-chlorophenyl)valine.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1)#[N:21].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:35][CH:34]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C(=O)OC)cccc2[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C(=O)OC)cccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a solution of methyl 2-butylbenzimidazole-7-carboxylate (1.5 g) in DMF (15 ml) was added sodium hydride (60% oil, 0.13 g) under ice-cooling. The mixture was stirred for 20 minutes and there was added 4-(2-cyanophenyl)benzyl chloride (1.5 g). The resultant mixture was stirred for further 5 hours at room temperature and there was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to give a pale yellow oil (2.3 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2cc3cc(Cl)ccc3nc2Cl)cc1
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc3cc(Cl)ccc3nc2Cl)cc1

Procedure:
Ethyl 2-{4-[(2,6-dichloroquinolin-3-yl)oxy]phenoxy}propionate was prepared by reacting 4-[(2,6-dichloroquinolin-3-yl)oxy]phenol and ethyl 2-bromopropionate following essentially the same procedure as that described in Example 1 part (c). The product was obtained as a solid, mp 56° C.
Reaction SMILES: Cl.ClCCN1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O-:14])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:14][C:6]1[CH:7]=[CH:8][C:9]([O:14][C:11]2[C:8]3[C:7](=[CH:6][C:11]([O:14][CH3:11])=[CH:10][CH:9]=3)[CH:8]=[CH:9][C:10]=2[C:8]2[CH:7]=[CH:6][CH:7]=[C:10]([O:14][CH3:11])[CH:9]=2)=[CH:10][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 320 %

Procedure:
A solution of 1.5 g (4 mmol) of 1-(4-hydroxyphenoxy)-2-(3-methoxyphenyl)-6-methoxynaphthalene in 40 mL of DMF was prepared. To this solution was added 920 mg (5 mmol) of 2-chloroethylpiperidine hydrochloride and 5.2 g (16 mmol) of Cs2CO3, the reaction was stirred at ambient temperature under a nitrogen atmosphere for sixteen hours. The solvents were removed by evaporation and the residue partioned between water and EtOAc. The EtOAc layer was washed with water, then brine, dried with Na2SO4, and evaporated to dryness. The residue was dissolved in 10 mL of MeOH and 1 mL of 5N HCl was added. The solvents were removed by evaporation and the product crystallized from EtOAc. This yielded 1.8 g of the title compound as a white solid, mp 161-162° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:20])[CH2:12][CH:13]([CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]([O:29][CH2:30][CH3:31])=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccc2ccccc2c1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-naphthalenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(2-naphthalenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[Br-].[CH2:14]([Zn+])[CH:15]([CH3:17])[CH3:16]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of methyl 4-bromo-3-fluorobenzoate (322 mg, 1.38 mmol) and isobutylzinc bromide (4.1 mL, 0.5 M in THF) in 10 mL of THF was added bis(tri-tert-butylphosphine)palladium(0) (14 mg, 0.03 mmol). The mixture was flushed with nitrogen three times and then stirred at rt overnight. The reaction was quenched by adding 5.0 mL of 1.0 N HCl solution and extracted with Et2O (3×20 mL). Organic layers were combined, washed with brine, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 1:99 v/v EtOAc/hexanes as the eluant afforded 243 mg (84%) of the title compound: 1H NMR δ 0.92 (d, J=6.6, 6H), 1.93 (m, 1H), 2.56 (d, J=6.1, 2H), 3.91 (s, 31H), 7.21 (t, J=7.6, 11H), 7.67 (dd, J=1.5, 10.2, 11H), 7.74 (dd, J=1.6, 7.8, 11H).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)=[CH2:29]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 92 %

Procedure:
The title compound II-ak was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.51 (m, 1H), 4.97 (m, 2H), 2.53-0.82 (m, 21H), 1.14 (s, 3H), 0.98 (s, 3H),
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]([NH2:12])=[S:11]>O1CCCC1>[S:11]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:9]=[C:10]1[NH2:12]
Reactant: NC(N)=S
Reactant: O=C1CCCCC1Cl
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CCCC2
Yield: 73 %

Procedure:
A stirred mixture of 2-chlorocyclohexanone (200 mg, 1.5 mmol) and thiourea (114 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was heated at reflux for 6 hours. The solution was concentrated under reduced pressure and the amine was purified by flash column chromatography using ethylacetate/hexane 1/1 as eluent to afford a colourless oil (169 mg, 74%).
Reaction SMILES: C(O)=O.[CH2:4]([O:6][C:7](=[O:54])[C@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[N:33]([CH2:44][CH2:45][O:46]CC3C=CC=CC=3)[CH2:34][CH2:35][O:36]CC3C=CC=CC=3)[CH:24]=2)[CH:18]=1)[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:5]>[OH-].[Pd+2].[OH-].C(O)C>[CH2:4]([O:6][C:7](=[O:54])[C@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[N:33]([CH2:44][CH2:45][OH:46])[CH2:34][CH2:35][OH:36])[CH:24]=2)[CH:18]=1)[NH:9][C:10](=[O:15])[C:11]([F:13])([F:14])[F:12])[CH3:5]
Reactant: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCOCc4ccccc4)CCOCc4ccccc4)cccc3c2)c1)NC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCO)CCO)cccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 74 %

Procedure:
Ethanol (10 ml), formic acid (1.94 ml, 52 mmol) and 20% palladium hydroxide (145 mg) were added to 3-[5-bis[2-(benzyloxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (739 mg, 1.03 mmol) and the mixture was heated under reflux for 3 days. After the mixture was cooled to room temperature, the catalyst was filtered off and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1 and 2) to give 3-[5-bis[2-(hydroxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (395 mg, 71%) as a dark yellow foam.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[N:12]=1>O.CC(C)=O>[Cl:18][C:13]1[CH:14]=[C:15]([Cl:17])[N:16]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1cc(Cl)nc(Oc2ccccc2)n1

Procedure:
Phenol (0.94 g, 10 mmol) and sodium hydroxide (0.44 g, 11 mmol) in water (20 ml) were added to 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in acetone (20 ml) at 0° C. The mixture was stirred over night. The precipitate then filtered through celite, then the most of the acetone was removed in vacuo. The resulting aqueous solution was extracted with ethyl acetate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified in silica to provide a colorless oil.