Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC(Br)C.Cl[Si](C)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[N:26][N:27]=2)[CH:24]=1>[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH2:10]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[N:26][N:27]=2)[CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Clc1ccccc1-c1nnc2ccc(Cc3ccccc3)cn12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a flame-dried flash under nitrogen was added Rieke zinc (2.3 mL, 1.75 mmol). The total volume of the reaction was brought to 5 mL using dry THF. To the slurry was added dibromoethane (10.0 μL, 0.01 mmol), and the reaction warmed to 65° C. for 3 minutes. The reaction was then cooled to 35° C., and chlorotrimethylsilane (30.0 μL, 0.25 mmol) added, and the resulting reaction stirred for 30 minutes at 35° C. Benzyl bromide (55 uL, 0.46 mmol), was added and the reaction stirred a further 30 minutes at 35° C. To the mixture was then added 6-bromo-3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine (136 mg, 0.44 mmol) and Pd(PPh3)4 and the temperature increased to 50° C. Flash chromatography purification (elution with 35-85% ethyl acetate/hexane), followed by preparatory HPLC (15-80% water/acetonitrile) of the crude reaction mixture yielded the title compound (10 mg, 7%). MS (M+1)=320.4.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: Cc1cccnc1CCl
Product: COCOc1cc(SCc2ncccc2C)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-(chloromethyl)-3-methylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
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].[CH:16]([O:19][CH2:20][CH2:21][NH2:22])([CH3:18])[CH3:17].C(N(CC)CC)C>>[CH:16]([O:19][CH2:20][CH2:21][NH:22][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])([CH3:18])[CH3:17]
Reactant: CC(C)OCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 88.4 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.16mmol), 2-aminoethyl isopropyl ether (0.533 g, 5.16 mmol) and triethylamine (1.42 mL, 10.32 mmol) were reacted to form the desired product (1.63 g, 89%). LC-MS (m/z) 357.0 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C(O)(=O)C>[Fe].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:17])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(C(F)(F)F)cs2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N)c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
The product from Step D (3.1 g, 0.011 mol) was suspended in a mixture of glacial acetic acid (15 mL) and water (5 mL). The mixture was heated on a steam bath to a temperature of 65° C. Iron powder (1.9 g, 0.035 mol) was then added in small portions (exothermic). Care was taken during the addition to ensure that the temperature did not exceed 75° C. Once the iron had been added, heating at 75° C. was continued for another 10 min. The reaction mixture was hot-filtered onto 30 g cracked ice. After the ice melted, the aqueous mixture was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated sodium bicarbonate and brine (30 mL each). The dried (MgSO4) solution was concentrated to furnish 1.4 g (53% yield) of the title compound as a white solid melting at 100°-103° C. 1H NMR (400 MHz, CDCl3) δ 7.62 (s,1H), 7.39 (s,1H), 7.03-7.05 (m,1H), 6.69-6.71 (m,1H), 5.82 (br s,2H), 2.28 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[NH:13][N:12](COCC[Si](C)(C)C)[NH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCN1NC=C(Nc2cccc(F)c2)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cccc(Nc2cn[nH]n2)c1
Temperature: 90 °C

Procedure:
To N-(3-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-amine 7e (50 mg, 0.16 mmol) was added ethane-1,2-diamine (50 mg, 55.6 μL, 0.83 mmol) and tetrabutylammonium fluoride (424 mg, 478 μL, 1.62 mmol) and the mixture was heated to 90° C. in a microwave for 2 h. The mixture was diluted with EtOAc and water and the organic was washed with water, brine and then dried (MgSO4) and concentrated. Material was purified by Fractionlynx to afford the title compound I-45 as a white solid (10 mg, 35%). 1H NMR (500 MHz, d6-DMSO) δ 14.19 (1H, s), 9.02 (1H, s), 7.39 (1H, d), 7.17-7.27 (2H, m), 6.99-7.06 (1H, m), 6.52-6.61 (1H, m). MS m/z: 179.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22](OC)=[O:23])=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[CH3:28][NH2:29]>>[F:18][C:10]1[C:9]([C:19]#[C:20][C:21]([OH:27])([C:22](=[O:23])[NH:29][CH3:28])[CH3:26])=[CH:8][C:7]2[C:6]3[N:16]([CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)[CH:17]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3
Reactant: CN
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Product: CNC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20-mL sealed tube, methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.32 mmol, 1.00 equiv) was added into a solution of methanamine (30% w/w in ethanol, 5 mL). The resulting solution was stirred for 8 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 35 mg (29%) of 8-Fluoro-9-(3-hydroxy-3-methylcarbamoyl-but-1-ynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a yellow solid. LC-MS: (ES, m/z): 373 [M+H]; 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.548 (d, 1H), 8.000-7.800 (m, 1H), 7.773 (s, 1H), 7.564 (br s, 1H), 7.108 (br s, 1H), 7.012 (d, 1H), 6.551 (s, 1H), 4.551-4.481 (m, 4H), 2.624 (d, 3H), 1.603 (s, 3H).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(c1ccccc1)N1CCOCC1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing morpholine (174 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.072, 72%). ESI-MS m/z calc. 427.1. found 428.0 (M+1)+ Retention time 2.40 minutes.
Reaction SMILES: C(C1[CH:19]=[CH:18][C:6]2[O:7][CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[CH:12][CH3:13])[C:5]=2[CH:4]=1)#N.[C:20]([OH:23])(=[O:22])[CH3:21].Cl>O>[CH:12](=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH2:8][O:7][C:6]2[CH:18]=[CH:19][C:21]([C:20]([OH:23])=[O:22])=[CH:4][C:5]1=2)[CH3:13]
Reactant: CC=C1c2ccccc2COc2ccc(C#N)cc21
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC=C1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Reflux a mixture of 2.8 gm of the nitrile of Step A, 50 ml of acetic acid, 5 ml of water and 5 ml of concentrated hydrochloric acid for 140 hours. Cool the reaction mixture, separate the solids by filtration and dry. Recrystallize from toluene to obtain the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(O[Na])(C)=O>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:14](=[O:16])[CH3:15])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2ccc(=O)oc2cc1O
Agent: CC(=O)O[Na]
Solvent: O
Product: CC(=O)Oc1cc2oc(=O)ccc2cc1C

Procedure:
To prepare the alkylangelicins with an alkyl group in the 4'-position of the furan ring, the suitable umbelliferones, (I), (II), (III) were acetylated and the 7-acetoxycoumarins thus obtained were submitted to the Fries rearrangement. The 8-acetylumbelliferones were converted into the ethyl esters of the 7-(8-acetylcoumarinyl)oxyacetic acids, which were then hydrolized and cyclized yielding the desired 4'-methylangelicins. In such a manner a mixture of 6-methyl-7-hydroxycoumarin (I) (10.0 g), acetic anhydride (40 ml) and anhydrous AcONa (4.0 g) was refluxed for 1 h. To the reaction mixture an equal volume of H2O was cautiously added and the whole was refluxed for 10 min. The mixture was diluted with H2O (300 ml), chilled and the precipitate was collected by filtration, washed several times with H2O, dried and crystallized from MeOH, yielding the 6-methyl-7-acetoxycoumarin (XXII) (10.0 g; m.p. 147° C.). ##STR28##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]3)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:34][CH2:33][CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][C:24]3[O:23][N:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:25]=3)[CH2:32][CH2:31]2)=[O:14])[CH:3]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: Nc1cc(C(=O)O)nc2ccccc12
Product: Nc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)nc2ccccc12

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 275 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using 1-{1-[(3-phenyl-5-isoxazolyl)methyl]-4-piperidinyl}methanaminethe compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate the title compound having the following physical data was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]([CH2:29][C:30](OC)=[O:31])[C:12]2[C:17]([C:18]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:16][CH:15]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:13]=2.C[O-].[Na+]>CO.CCOC(C)=O>[CH:19]1([C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=3[N:11]3[CH2:29][C:30](=[O:31])[NH:1][CH2:2][C:3]4[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=4[C:10]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)Cn1c(-c2ccc(F)cc2CN)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)NCc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[2-(aminomethyl)-4-fluorophenyl]-3-cyclohexyl-1-(2-methoxy-2-oxoethyl)-1H-indole-6-carboxylate (1 eq., from Step 3) in dry MeOH (0.05 M), 10% in weight of sodium methoxide was added and the mixture stirred at RT overnight. The volume of the solution was reduced in vacuo, before diluting with EtOAc. The organic phase was washed with HCl 1 N and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (83%); MS (ES+) m/z 421 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[C:4]([C:21]2[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)=[CH:3]1.[OH-].[Na+].CO.Cl>O>[OH:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:21]3[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(OS(=O)(=O)c5ccccc5)ccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(C2=C(c3cn(C)c4cc(O)ccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
3-(6-hydroxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione was prepared by treating Benzenesulfonic acid 1-methyl-3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-6-yl ester (141 mg 0.28 mm) with 4N NaOH (0.5 mL, 2 mmol) and CH3OH (4 mL) and heating to reflux temperature for 6 hours. After cooling to room temperature, the reaction mixture was diluted with H2O, acidified with 2N HCl, and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to afford, after purification by flash column chromatography 3-(6-hydroxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (15 mg); mp=279°-282° 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.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:18]=[O:19]
Reactant: c1ccc2scnc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2s1
Reaction time: 0.33 h

Procedure:
To a stirred solution of benzothiazole (3.28 ml) in anydrous THF (40 ml), at −78°, under a nitrogen atmosphere, butyllithium (2.0 ml of a 1.6M solution in hexane) was added dropwise. After 0.33 h, a solution of DMF (7 ml) in anydrous THF (20 ml) was added dropwise and the reaction mixture was allowed to rise to 0° over 1 h. The reaction was quenched by pouring the mixture into water (100 ml) and extracted with EE (2×150 ml). The organic layer was washed with brine, dried and the solvent evaporated under reduced pressure. The crude residue was purified by flash chromatography (eluting with CH-EA in gradient from 95:5 to 8:2), and crystallized from PE to give the title compound as a yellow solid (1.88 g). M.p. 76-77°
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C@@H:24]1[CH2:28][C@@H:27]([CH3:29])[C:26](=[O:30])[O:25]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C(N)CCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[C@@H:24]([OH:25])[CH2:28][C@H:27]([C:26](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:29])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1C[C@@H]([C@H](Cc2cccc(OCc3ccccc3)c2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CCCCN
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 188.6 %

Procedure:
[(S*)-2-(3-Benzyloxy-phenyl)-1-((2S*,4R*)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester (4.0 g, 9.4 mmol) is dissolved in butylamine (200 ml) and stirred for 18 h in an heating bath of 90° C. The butylamine is evaporated and the residue is recrystallized from DCM/ether/hexane to give white crystals (4.42 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH:28]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH2:28][NH:8][C:5]2[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: Nc1cnc(Br)cn1
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CCNc2cnc(Br)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 5-bromo-2-pyrazinamine (0.35 g, 2.01 mmol) in 1-2 dichloroethane (DCE, 5.0 mL) was added a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.722 g, 2.41 mmol) in DCE (2.0 mL), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3.0 eq.) was then added in one portion and reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with DCM (5 mL), quenched with 2 M of NH4OH in water. The layers were separated, and the aqueous layer was extracted with DCM (5.0 mL×2). The combined organic layers were washed with aqueous NaHCO3 (15 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.85 g (77%) of title compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([Cl:30])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccncc1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccncc1
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-4-yl-propionic acid ethyl ester (0.68 g, 2.0 mmol) (from Example 9a supra) and aniline (3.0 mL) (Aldrich) was heated at 120° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-4-yl-propionic acid ethyl ester as a brown solid which was used in the next step without further purification. (Yield 0.54 g, 83.1%).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].IN1C(=O)CCC1=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([N:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:34]=3)=[CH:29][C:28]2=[O:46])[CH2:22][O:23][CH2:24]SC)=[CH:17][C:16]=1[F:47]>CN(C=O)C>[P:1]([OH:4])([OH:3])([O:2][CH2:24][O:23][CH2:22][C@H:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:47])[CH:17]=1)[N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[N:34]=2)=[CH:29][C:28]1=[O:46])=[O:5]
Reactant: CSCOC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Reactant: O=P(O)(O)O
Agent: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](COCOP(=O)(O)O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
Phosphoric acid (0.40 g, 3.98 mmol), 4 Å molecular sieves (5 g) and N-iodosuccinimide (0.46 g, 1.99 mmol) were added to (S)-1-(1-(4-chloro-3-fluorophenyl)-2-((methylthio)methoxy)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.50 g, 1.00 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with sodium thiosulfate. Sodium carbonate was added to bring pH to 10, and the solvent was removed. The resultant was purified by HPLC to afford (S)-(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethoxy)methyl dihydrogen phosphate (13 mg). M+1=555.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:33]C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[OH:33][C:13]1[CH:12]=[C:11]2[C:16]([C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:20][CH:19]=3)[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-3-(4-fluorophenyl)-7-methoxy-4-(4-(2-piperidinoethoxy)phenyl)chromane (0.923 g, 2.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as a colourless, amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([O:17][C:18]3[CH:33]=[CH:32][C:21]([C:22]([O:24]CC4C=CC=CC=4)=[O:23])=[CH:20][CH:19]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2.O1CCOCC1>[Pd].C(OCC)C>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:32][CH:33]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: [Pd]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Oc3ccc(C(=O)O)cc3)ccc21
Reaction time: 3 h
Yield: 70.8 %

Procedure:
2.4 g (5.2 mmol) of benzyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetoxy)benzoate, 1 g of palladium on charcoal (5%) and 100 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 7 bars for three hours, the catalyst is filtered off and washed with twice 50 ml of THF and the filtrates are evaporated. The residue obtained is ground in the minimum amount of ethyl ether, filtered off and dried. 1.35 g (70%) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetoxy)benzoic acid, melting point 142°-143° C., are obtained.