Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23]>CN(C)C=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:15][C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Under N2 in a 1 L round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 51.1 g (370 mmol) of K2CO3 and 20.1 g (123 mmol) of 3,4-dichlorophenol (Aldrich Chem. Co., Milwaukee, Wis.) in 500 mL of anhydrous N,N-dimethylformamide (DMF). After stirring the mixture for 30 min., 25 g (123 mmol) of 5-bromo-2-fluoro-benzaldehyde (Aldrich) in 150 mL of DMF was added and the mixture was heated to 90-100° C. overnight. After allowing the reaction to cool to room temperature, the mixture was concentrated at reduced pressure on a rotary evaporator and the resulting oily residue was then diluted with water and EtOAc. The aqueous layer was then extracted with additional EtOAc and the organic layers were combined, washed with H2O and saturated NaCl and dried over Na2SO4. Removal of the solvent in vacuo gave a light yellow oil which was further dried under vacuum overnight to give the title product as a pale yellow solid, 40.2 g; m.p. 129-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]#[N:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]#[N:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1c(N)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1c(NC(=O)c2ccccc2)ccc2ccccc12

Procedure:
3.0 g (17.8 millimoles) of 2-aminonaphthalene-1-carbonitrile (Chem. Pharm. Bull 33 (4) (1985), 1360-1366) were stirred with 2.5 g (18.1 millimoles) of benzoyl chloride and 4 ml of triethylamine in 100 ml of toluene for 15 hours at 80° C. After the end of the reaction, the product was filtered off and dried. 1.5 g (31% of theory) of the title compound of melting point 205° C. (active ingredient example 1008) were obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]4[O:25][C:26](=[O:29])[CH2:27][N:28]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C)C=O.O>[CH:36]1([CH2:35][NH:34][C:26](=[O:29])[CH2:27][NH:28][C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=3)=[CH:15][CH:16]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C1CN=C(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)O1
Reactant: NCC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)NCC1CC1
Temperature: 150 °C

Procedure:
A mixture of 2-[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]-5(4H)-oxazolone (i.e. the title product of Step A) (50 mg) and (aminomethyl)cyclopropane (0.1 mL) in N,N-dimethylformamide (1 mL) was irradiated with microwave radiation to maintain a temperature around 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2 to 3:7) as eluent to afford the title compound, a compound of the present invention, as a pale yellow solid (47 mg, 82% yield).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
A mixture of 28.16 g (0.132 mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of 3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMF is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2quinolinylmethyloxy)benzoic acid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:3]1([CH2:2][CH2:1][NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: NCCc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NCCC1CCCCC1

Procedure:
Phenethylamine (50 g) was dissolved in 1000 mL of glacial acetic acid in a pressure vessel, followed by addition of platinum oxide (15 g). After shaking under 4 atm of hydrogen for 48 h, the reaction was filtered and the acetic acid was removed under reduced pressure. The residue was taken up in water (1000 mL), basified with 5N NaOH, and washed with ether (5×250 mL). The ether extracts were washed with brine (250 mL), dried (MgSO4), filtered and concentrated to afford a light yellow oil which was purified by fractional distillation at atmospheric pressure (bp 185° C., 49.5 g, 94%).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=O)[C:9]=2[CH:10]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[N:13][OH:14])[C:9]=2[CH:10]=1
Reactant: O=C1CCCc2[nH]c(Br)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCCc2[nH]c(Br)cc21
Yield: 114.6 %

Procedure:
A solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a) (222 mg, 1.04 mmol), hydroxylamine hydrochloride (80 mg, 1.14 mmol), and sodium acetate (94 mg, 1.14 mmol) in MeOH (28 mL) was stirred under argon at 50° C. for 22 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (60 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (273 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm: (˜2:1 mixture of oxime isomers) Major isomer: 7.99 (1H, br. s.), 6.36 (1H, br. s.), 2.71 (2H, br. s.), 2.63 (2H, br. s.), 1.89-1.98 (2H, m). Minor isomer: 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, br. s.), 6.97 (1H, br. s.), 2.67-2.75 (2H, m), 2.47 (2H, br. s.), 1.99 (2H, br. s.). m/z (ESI, +ve) 228.9/231.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]([OH:16])=O)([CH2:11]3)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:78]=[CH:77][C:52]([O:53][C:54]2[CH:59]=[CH:58][N:57]=[C:56]3[CH:60]=[C:61]([C:63]4[CH:68]=[CH:67][C:66]([C:69]([N:71]5[CH2:76][CH2:75][O:74][CH2:73][CH2:72]5)=[O:70])=[CH:65][CH:64]=4)[S:62][C:55]=23)=[C:51]([F:79])[CH:50]=1>ClCCl>[F:79][C:51]1[CH:50]=[C:49]([NH:48][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]3=[O:17])=[O:16])[CH:78]=[CH:77][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[CH:60]=[C:61]([C:63]3[CH:64]=[CH:65][C:66]([C:69]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[O:70])=[CH:67][CH:68]=3)[S:62][C:55]=12
Reactant: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)c3s2)cc1)N1CCOCC1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (20 mg, 0.085 mmol) in 500 uL of dichloromethane at room temperature under nitrogen was added HOBt (19.5 mg, 0.128 mmol), EDCI (24.5 mg, 0.128 mmol) and DIEA (45 uL, 0.225 mmol). After 15 minutes a solution of (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A, 34 mg, 0.077 mmol) in 500 uL dichloromethane was added by pipet. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed 1×30 mL with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto Biotage 12S column and eluted initially with dichloromethane and then after about 100 mL of elution, switched to 2/98 MeOH/dichloromethane. Pure product containing fractions were pooled and concentrated to a white glass (12 mg, 21% yield). LRMS (APCI pos) m/e 667.4 (M+1). 1H NMR: (CDCl3, 400 MHz): δ 10.52 (s, 1H), 8.50 (d, 1H), 7.83 (m, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.54-7.46 (m, 4H), 7.31 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.52 (d, 1H), 4.12 (m, 1H), 3.90-3.60 (br m, 8H), 3.78 (d, 1H), 2.81 (m, 1H), 2.05 (m, 1H), 1.39 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (10 g, 32.0 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (10.3 g, 48.0 mmol) to afford the desired product (12.8 g, 81%) as an off-white solid: ESI MS m/z 491 [C24H32BrN3O3+H]+.
Reaction SMILES: C(O[C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13]C(=O)C)=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20](=[O:22])[CH3:21])(=O)C.C[C:24](P(OC)(O)=O)([C:26]([O-:28])=[O:27])C>>[OH:13][C:8]1[C:7]([CH3:17])=[C:6]2[C:5](=[C:10]([CH3:11])[C:9]=1[CH3:12])[O:22][C:20]([CH3:21])([CH2:24][C:26]([OH:28])=[O:27])[CH2:19][CH2:18]2
Reactant: CC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2

Procedure:
By the procedure described in Example 6, (±)-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-one was treated with the anion from trimethylphosphonoacetate. The crude (±)-methyl 5-(2,5-diacetoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenoate thus obtained, upon saponification with base as in Example 6, yielded (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid as a light tan powder, m.p. 169°-171.5°.
Reaction SMILES: O[CH:2](C)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.F[C:25](F)(F)[C:26]([OH:28])=[O:27]>O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([CH:3]([CH3:2])[CH2:25][C:26]([OH:28])=[O:27])=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(O)Cc1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 0.33 h

Procedure:
4 ml. of formic acid are added over 20 minutes to a solution of 2.3 g. of 4-(2-propneyl)-2',4'-difluorobiphenyl, obtained by eliminating water from 4-(2-hydroxypropyl)-2',4'-difluorobiphenyl with polyphosphoric acid, in a mixture of 12 ml. of sulfuric acid and 8 ml. of trifluoroacetic acid. After 20 minutes more, the mixture is poured into water to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: NN
Reactant: Cc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methylphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (521 mg, 1.1 mmol) produced in Synthesis Example 30 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 183 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methylbenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (496 mg, yield 96%).
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]2[CH:18]([NH:2][N:1]=[C:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:17]1=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C1=NNC2C(=O)N(Cc3ccccc3)C(=O)C12
Reaction time: 18 h
Yield: 100 %

Procedure:
Ethyl diazoacetate (13 g, 114 mmol) in diethyl ether (100 ml) was added dropwise to a solution of N-benzylmaleimide (10 g, 53 mmol) in diethyl ether (250 ml). The resulting mixture was allowed to stir for 18 hours; the solvent was then removed in vacuo, and the resulting residue partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated to provide the title product as a white solid, mp 145°-146° with decomposition (16 g, 53 mmol, 100% yield). 1H NMR (CDCl3): 7.31 (m, 5H), 7.02 (bs, 1H), 4.89 (dd, J=11, 2 Hz, 1H), 4.65 (s, 2H), 4.55 (d, J=10 Hz, 1H), 4.36 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:36])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:26][CH2:25][C@H:24]5[C@@H:20]4[CH2:21][CH2:22][C@H:23]5[CH:27]([C:32]([O:34]C)=[O:33])[C:28]([O:30]C)=[O:29])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[C:8](=[O:36])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:26][CH2:25][C@H:24]5[C@@H:20]4[CH2:21][CH2:22][C@H:23]5[CH:27]([C:28]([OH:30])=[O:29])[C:32]([OH:34])=[O:33])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C(C(=O)OC)[C@@H]1CC[C@H]2[C@@H]1CC[C@H]2c1ccc(N2CCOc3ncnc(N)c3C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1C(=O)N(c1ccc([C@@H]3CC[C@H]4[C@@H]3CC[C@H]4C(C(=O)O)C(=O)O)cc1)CCO2

Procedure:
(±)-{(1R,3aS,4R,6aS)-4-[4-(4-Amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]octahydropentalen-1-yl}malonic acid was prepared as follows. A solution of dimethyl(±)-{(1R,3aS,4R,6aS)-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]octahydropentalen-1-yl}malonate (190 mg, 0.38 mmol) and lithium hydroxide monohydrate (166 mg, 3.9 mmol) in p-dioxane/water (8:3-11 mL) was stirred at 50° C. for 3 hours. The reaction was concentrated to remove the p-dioxane, water (2 mL) added and the mixture extracted with EtOAc (5 mL). The aqueous layer was adjusted to pH˜3 with 2N aqueous hydrochloric acid, the solids filtered and dried in vacuo to afford the title compound as a white solid, 179 mg. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.58 (br s, 2H), 7.13 (d, 2H), 7.10 (d, 2H), 4.57 (m, 2H), 3.95 (m, 2H), 3.08 (d, 1H), 2.64 (m, 1H), 2.39 (m, 2H), 2.24 (m, 1H), 1.87-1.10 (m, 7H). m/z=467.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[CH3:2].[C:12](#[N:15])[CH:13]=[CH2:14].CC[O-].[Na+]>>[C:12]([CH2:13][CH2:14][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[O:3][CH2:1][CH3:2])#[N:15]
Reactant: C=CC#N
Reactant: CCOP(O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOP(=O)(CCC#N)c1ccccc1
Reaction time: 1 h

Procedure:
To 42.45 g of phenylphosphonous acid-ethylester and 16.45 ml of acrylonitrile are added with stirring 5 ml of sodium ethylate (1 molar). The reaction is exothermic. After 1 hour stirring at 20° the mixture is fractionally distilled. There is obtained ethyl 2-cyanoethyl(phenyl)phosphinate as a colorless oil, b.p. 134°-136°/7 Pa.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>C(O)C(F)(F)F>[CH3:14][C:12]1[C:11](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Solvent: OCC(F)(F)F
Product: CC1=N[C@H](c2ccccc2)COC1=O
Yield: 41 %

Procedure:
(R)-2-phenylglycinol (3.00 g, 21.9 mmol, 1.0 equiv.) and ethyl pyruvate (2.67 mL, 24.1 mmol, 1.1 equiv.) were refluxed in trifluoroethanol (50 mL) over activated 4 molecular sieves (8.00 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (7:3) to furnish the title compound as a white solid (1.70 g, 41%); mp 71.0-72.0° C. (lit 71.0-72.0° C.); v(max) (KBr) 3001 (C—H), 1734 (C═O), 1642 (C═N) cm−1; δH (250 MHz, CDCl3) 7.42-7.32 (5H, m, Ph), 4.89-4.80 (1H, m, PhCH), 4.56 (1H, dd, /4.49 Hz, T 11.55 Hz, 6β-H), 4.25 (1H, dd, J 10.97 Hz, T 11.51 Hz, 6α-H), 2.40 (3H, s, CH3); δC (62.5 MHz, CDCl3) 160.7, 155.9, 137.2, 129.4, 128.7, 127.5, 71.9, 60.1, 22.2; m/z (CL, NH3), 189 (M+, 25%), 159 (12%), 130 (24%), 104 (100%), 90 (21%), and 78 (6%); HRMS for C11H11NO2 requires 189.0787 found 189.0782. [α]D20 −2560.0 (c 1.11 CHCl3) (lit [α]D20 −237.1 (c 1.11 CHCl3)).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([O:15]C)=[CH:6][CH:5]=2.B(Br)(Br)Br.C(Cl)Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([OH:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(Cl)n2Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Cc1c(Cl)n(Cc2ccccc2)c2ccc(O)cc12
Reaction time: 1.5 h
Yield: 103.4 %

Procedure:
A solution of 140 mg (0.43 mmol) of 2-chloro-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 11) in 20 mL of methylene chloride was treated with 2 mL of 1M BBr3 /CH2Cl2, stirred for 1.5 hours, stirred with aqueous HCl, the CH2Cl2 solvent separated, and washed with water, saturated NaCl solution and dried (Na2SO4). On concentrating at reduced pressure, there was obtained 140 mg of crude 2-chloro-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide. This material was dissolved in 15 mL of DMSO, 20 mg of 60% NaH/mineral oil added, and after 5 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. The reaction mixture was heated by oil bath at 70° C. for 70 minutes. After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution and dried (Na2SO4). After concentrating, a residue was obtained that was chromatographed on silca (eluted with CH2Cl2 →3% MeOH/CH2Cl2) to give 105 mg of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (105 mg) was dissolved in 15 mL of EtOH, 1 mL of 5N NaOH added, and the solution stirred for 18 hours. The mixture was made acidic with 5N HCl, and extracted with EtOAc. The EtOAc solution was washed with saturated NaCl solution, dried (Na2 SO4) and concentrated at reduced pressure. The residue was dissolved in MeOH/CH2Cl2, the solution concentrated, to give 75 mg (80% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-chloro-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 198°-200° C.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12]2)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)C(F)(F)F)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CC2CCC(C1)N2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1.0 mmol) in DCM (4 mL) were added triethylamine (208 μL, 1.5 mmol) and trifluoroacetic anhydride (169 μL, 1.2 mmol) at 0° C. and the mixture stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography to give 3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a colourless oil. To a solution of 3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in DCM (4 mL) was added TFA (1 mL) and the solution stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a colourless oil (212 mg, 66%).
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C>Cl>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][CH:9]([P:4]([OH:8])(=[O:3])[OH:5])[P:10]([OH:14])(=[O:11])[OH:15]
Reactant: CCOP(=O)(OCC)C(Nc1nccs1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Temperature: 25 °C

Procedure:
6.57 g (17 mmol) of 1-(thiazol-2-ylamino)-methane-1,1-diphosphonic acid tetraethyl ester are dissolved in 70 ml of N hydrochloric acid and heated under reflux for 6 hours. In the course of the reaction, the product separates out in the form of a fine white precipitate. After cooling to room temperature, filtration is carried out and the product is washed with aqueous methanol. 4.33 g (93% of the theoretical yield) of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275° (decomposition) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C2CCNCC2)cc1
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To a stirring solution of tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate (388 mg, 0.99 mmol) and triethylsilane (791 μl, 4.95 mmol) in DCM (2 mL) cooled to −30° C. was slowly added 2,2,2-trifluoroacetic acid (379 μl, 4.95 mmol) in a drop-wise fashion. The reaction mixture was allowed to warm slowly and stirring continued for 16 h. The reaction mixture was poured onto ice-water/NaOH (50 mL/5 mL, 2 M) and extracted with DCM (3×20 mL). The combined organic extracts were washed successively with water (50 mL) and NaHCO3 (20 mL), dried over MgSO4 and evaporated to afford 166 mg (58%) of 4-(4-(heptyloxy)phenyl)piperidine INT-19 as a white, waxy solid. LCMS-ESI (m/z) calculated for C18H29NO: 275.4. found 276.0 [M+H]+, tR=2.88 min. (Method 11).