Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@@H:21]1[C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:22][C@@H:21]1[C:31]([OH:33])=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
A solution of the product from Example 1, step (b) (0.43g) in ethanol (100ml) was treated with 10% palladium on charcoal (0.lg) and stirred in a pressure vessel under hydrogen at 3 atmospheres at room temperature for 3 days. The catalyst was filtered off and the filtrate evaporated. The residue was triturated with a mixture of ether and petroleum ether (bp 40°-60°) to give the title product (0.19g) as a pale grey, non-crystalline solid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Br[CH2:6][C:7]#[C:8][CH2:9][N:10]([CH3:15])[C:11](=[O:14])[O:12][CH3:13]>>[CH3:13][O:12][C:11](=[O:14])[N:10]([CH2:9][C:8]#[C:7][CH2:6][N:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: C1CNC1
Reactant: COC(=O)N(C)CC#CCBr
Product: COC(=O)N(C)CC#CCN1CCC1
Reaction time: 1 h

Procedure:
A solution of methyl[4-(diethylamino)-2-butynyl]- methyl-carbamate (4.2 g, 0.02 mol) (Example 1i) in anhydrous diethyl ether (50 ml) is added dropwise at room temperature to a stirred solution of cyanogen bromide in anhydrous diethyl ether (40 ml). The mixture is allowed to stand for 12 hours and the diethyl ether layer is separated, washed with water (40 ml), dried over magnesium sulfate, and concentrated. The resulting oil is then purified by bulb to bulb distillation under high vacuum to give methyl N-(4-bromo-2-butynyl)-N-methylcarbamate as a ight yellow oil. Azetidine (2 g, 0.032 mol) is added to a stirred solution of methyl N-(4-bromo-2-butynyl)-N-methylcarbamate (3.6 g, 0.016 mol). The mixture is kept at room temperature for one hour and then filtered. The filtrate is concentrated and the resulting oil purified by bulb to bulb distillation under high vacuum to give a light yellow oil. NMR(CDCl3): 4.10 (brs, 2H); 3.7 (s, 3H); 3.39 (brs, 2H); 2.94 (s, 3H); 2.45 (brs, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[H-].[Na+].Br[CH2:39][CH:40]1[CH2:43][CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:26]([CH2:39][CH:40]5[CH2:43][CH2:42][CH2:41]5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: BrCC1CCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CCC3)C(=O)CO4)cc2)CCC1
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (44 mg, 0.09 mmol) in dry DMF (1 ml) was added sodium hydride (9 mg, 0.22 mmol) and (bromomethyl)cyclobutane (130, 0.11 mmol) under nitrogen. The resulting mixture was stirred for 1 h at 80 C. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (8 mg, 16%). 1H NMR (500 MHz, CDCl3): 7.23-7.17 (8H, m), 7.13-7.11 (2H, m), 4.95 (1H, s), 4.80 (2H, s), 3.96 (2H, d), 2.68-2.64 (1H, m), 2.52-2.20 (4H, m), 2.00-1.95 (3H, m), 1.86-1.50 (5H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cccc(Cl)c2F)CCN(C(=O)OC(C)(C)C)C1
Yield: 76.7 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (8.05 g, 25.5 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 1.53 g, 38.2 mmol), iodomethane (3.17 mL, 51 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (6.45 g, 77%). MS m/z (rel. intensity, 70 eV) 256 (19), 228 (15), 199 (23), 187 (28), 57 (bp).
Reaction SMILES: O[C:2]1[C:7]2=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)[N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:63]([NH2:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C1COCC1>[CH2:63]([NH:70][C:2]1[C:7]2=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)[N:3]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cncc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
5-(4-Hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.100 g, 0.272 mmol) was dissolved in THF (10 mL) and BOP reagent (0.181 g, 0.408 mmol) and DIPEA (0.143 mL, 0.817 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Benzylamine (0.0440 g, 0.408 mmol) in THF (3 mL) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water was added (30 mL). The resulting aqueous solution was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep HPLC (Condition B-61 as described in general methods) to obtain 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0250 g, 20.1%). LCMS Condition B-38: retention time 2.08 min, [M+1]=457.2. HPLC Condition B-5: retention time 20.11 min, Purity 97.00%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (d, J=5.6 Hz, 2H), 6.76 (t, J=5.6 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.30 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.40-7.45 (m, 3H), 7.48 (t, J=7.6 Hz, 2H), 7.55 (dd, J=1.6, J=3.4 Hz, 2H), 7.68 (br s, 2H), 7.95 (d, J=2.4 Hz, 1H), 8.94 (t, J=2.2 Hz, 1H), 9.05 (d, J=2.4 Hz, 1H), 9.53 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:24][C:25](=O)[CH2:26][C:27](=O)[CH3:28]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH3:28])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(C(F)(F)F)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-(4-trifluoromethyl-phenyl)-amine and 2,4-pentanedione.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Br:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Br:16][C:17]1[N:18]=[CH:19][N:20]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:15])[N:3]=2)[CH:21]=1
Reactant: Brc1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.91 g, 8.0 mmol) and commercially available 4-bromo-imidazole (1.76 g, 12.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (2.76 g, 98%). MS (ISP) 349.1 [(M+H)+]; mp 176-178° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCn1ccc(N)n1
Solvent: CC#N
Product: N#CCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
2,2,2-Trifluoroethylisothiocyanate (3.4 g.) was added to a solution of 3-amino-1-(2-cyanoethyl)pyrazole (2.72 g.) in acetonitrile (10 ml.) and the solution left at room temperature for 18 hours. The mixture was evaporated to dryness and the residue recrystallised from ethanol to give 3-[3-(2,2,2-trifluoroethyl)thioureido]-1-(2-cyanoethyl)pyrazole, m.p. 164°-165°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: NCCCO
Reactant: O=Cc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OCCCNCc1ccccc1Br

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloroethane (0.4 M) at RT under nitrogen was added 3-aminopropanol (1.5 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (4 eq). After 5 hr the reaction was carefully quenched with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. EI-MS m/z 245 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH2:9]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
10 g of 3,4-difluoronitrobenzene was dissolved in 20 g of methanol and 10 g of concentrated hydrochloric acid and 2 g of iron powder were added thereto. The mixture was stirred at 60° C. for two hours, and then distilled to obtain 3,4-difluoroaniline. The reduction yield was 86%. To this product, 70 g of 36% hydrochloric acid was added to convert it into its salt. Under stirring, 18 g of a 25% NaNO2 aqueous solution was added at 0° C. to obtain a diazonium salt. The diazonium salt was dropwise added to a hydrochloric acid solution of cupric chloride heated to 120° C., for thermal decomposition. The diazotization yield was 84%. 3,4-Difluorochlorobenzene was obtained in an overall yield of 72%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCc1ccc(Oc2cc(O)ccc2C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(Oc3ccc(C(F)(F)F)cc3Br)ccc2C)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
A mixture of 3-[4-(5-hydroxy-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (Example 84, Step D) (0.46 g, 1.46 mmol), 3-bromo-4-fluorobenzotrifluoride (0.35 g, 1.45 mmol) and 325 mesh potassium carbonate (0.21 g, 1.52 mmol) in dry DMSO (10 mL) is heated to 100° C. and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0.633 g (81%) of the title compound. Rf=0.38 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:39]1[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:36])([CH3:37])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=1.45 min, m/z=488; 1H NMR (CDCl3) 7.68(dd, 1H), 7.52 (d, 1H), 7.32 (q, 2H), 7.17 (d, 2H), 7.06 (t, 2H), 6.97 (d, 2H), 6.91 (d, 1H), 5.66 (q, 1H), 3.72 (s, 3H), 2.99 (dt, 1H), 2.48 (dd, 2H), 2.27 (m, 1H), 2.11 (s, 2H), 1.55 (d, 3H), 1.44 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:20](Cl)([Cl:22])[Cl:21]>>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][CH:10]([O:13][P:20]([Cl:22])[Cl:21])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: ClP(Cl)Cl
Product: ClP(Cl)OC1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
A process for preparing (4,4-diphenylcyclohexyl)phosphooxymethyl diethylene triaminepenta-acetic acid comprising the steps of: (a) phosphorylating 1.0 equivalents of 4,4-diphenylcyclohexanol with about one equivalent of phosphorous trichloride to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula: ##STR20## (b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenycyclohexyloxy-diimidazolylphosphine having the formula: ##STR21## where imido refers to imidazolyl (c) coupling of the 4,4-diphenylcyclohexyloxy- diimidazolylphosphine formed in step (b) with from about 0.75 to about 1.0 equivalents of hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA -oxy, penta tert-butyl ester) imidazolyl-phosphine having the formula: ##STR22## where imido refers to imidazolyl (d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester) imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form (4,4-diphenylcyclohexyl)phosphonooxymethyl diethylene triamine, penta t-butyl ester having the formula: ##STR23##
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[N:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][NH:33]3)=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[N:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2nc(Nc4ccc(N5CCN(C6COC6)CC5)cc4)c4nc[nH]c4n2)c1CO)CCCC3
Temperature: 30 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 117h (140 mg, 0.20 mmol) and lithium hydroxide (48 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 117 (85 mg, 64%) as a white solid. MS-ESI: [M+H]+ 664.4. 1H NMR (500 MHz, CDCl3) δ 12.45 (s, 1H), 8.26 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 2H), 6.88 (s, 1H), 4.74-4.68 (m, 4H), 4.66-4.60 (m, 2H), 4.17-4.09 (m, 3H), 3.91-3.90 (m, 1H), 3.59 (t, J=6.5 Hz, 1H), 3.25-3.23 (m, 4H), 2.59-2.52 (m, 8H), 1.89-1.80 (m, 4H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH:20][C:22](=[O:24])[CH3:23])[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(CN)cc3C2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
14.5 g of g of 2-(p-toluenesulfonyl)-5-aminomethylisoindoline was dissolved in 200 ml of chloroform. 6.13 g of acetic anhydride was added dropwise to the solution under ice cooling while stirring. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was recrystallized from n-hexane to give 16.3 g of 2-(p-toluenesulfonyl)-5-acetamidomethylisoindoline.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.C(O)(=O)C>C(O)C>[NH2:18][C:5]1[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:3][C:2]([Br:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Br)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(Br)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 60 °C

Procedure:
In 25 ml of ethanol was dissolved 550 mg of 2-bromo-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, whereto 0.36 g (5 eq.) of reduced iron was added, followed by heating to 60° C. After 1.5 ml (16 eq.) of acetic acid was added dropwise, the mixture was refluxed for 1 hour.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH:1]1([NH:5][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a stirred solution of cyclobutylamine (0.400 g, 5.6 mmol), N,N-diisopropylethylamine (0.930 mL, 5.6 mmol) and pyridine (0.455 mL, 5.6 mmol) in methylene chloride (10 mL) at 0° C. was slowly added methanesulfonyl chloride (0.435 mL, 5.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexane) to afford the product as a low melting solid (0.82 g, 98%). 1H NMR (300 MHz, CDCl3) δ 4.62 (br s, 1H), 3.94 (m, 1H), 2.94 (s, 3H), 2.50-2.30 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.ClC1C=CC(I)=C(C=1)C(Cl)=O.Cl.[CH3:28][NH:29][O:30][CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:29]([O:30][CH3:31])[CH3:28])=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: Cl
Agent: O=C(Cl)c1cc(Cl)ccc1I
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)ccc1I
Temperature: 25 °C
Yield: 95.2 %

Procedure:
5-Chloro-2-iodobenzoic acid (2.8 g, 10 mmol) was taken up in dry methylene chloride (80 mL) and DMF (50 μL, cat.) followed by thionyl chloride (2.4 g, 20 mmol) were added. The mixture was stirred at reflux for 12 h, cooled to room temperature and evaporated in vacuo. The residue was azeotroped with toluene (2×10 mL) and used without further purification. The 5-chloro-2-iodobenzoyl chloride (10 mmol) was taken up in dry methylene chloride (50 mL) and N,O-dimethylhydroxylamine hydrochloride (1.1 g, 11 mmol) was added. The mixture was cooled to 0° C., and pyridine (2.4 g, 30 mmol) was added. The mixture was allowed to warm to room temperature, stir for 12 h, and was then quenched with saturated brine (20 mL). The organic phase was separated and the water phase was extracted with methylene chloride (2×10 mL). The combined organic extracts were dried with anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified using flash chromatography on silica gel (50 g) using methylene chloride as eluent to provide 5-chloro-2-iodo-N-methoxy-N-methylbenzamide (3.1 g, 95%) MS m/z=326 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]=[C:7]3[C:33]4[CH:39]=[C:38]([OH:40])[CH:37]=[CH:36][C:34]=4[O:35][C:5]=1[C:6]=23)([O-])=O>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:8]=[C:7]3[C:33]4[CH:39]=[C:38]([OH:40])[CH:37]=[CH:36][C:34]=4[O:35][C:5]=1[C:6]=23
Reactant: O=[N+]([O-])c1ccc2c3c(nn2CCN(CCOCc2ccccc2)Cc2ccccc2)-c2cc(O)ccc2Oc13
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc2c3c(nn2CCN(CCOCc2ccccc2)Cc2ccccc2)-c2cc(O)ccc2Oc13
Reaction time: 8 h

Procedure:
A mixture of 10 g of 5-nitro-2-[2-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]ethyl]-2H-[1]benzopyrano[4,3,2-cd]indazol-9-ol and 5 g of Raney nickel in 150 ml N,N-dimethylformamide was stirred at atmospheric pressure under hydrogen overnight. The mixture was filtered and the filtrate was concentrated in vacuo to a thick oil. The 5-amino-2-[2-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]ethyl]-2H-[1]benzopyrano[4,3,2-cd]indazol-9-ol so obtained was used without further processing.