Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:15]1([O:14][CH2:13][CH2:12][S:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:10][CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(=O)c1ccc(SCCOC2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(SCCOC2CCCCCCC2)cc1
Yield: 93.3 %

Procedure:
A solution of 4-[[2-(cyclooctyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (0.96 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (3.5 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.86 g of purified 4-[[2-(cyclooctyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid as a yellow solid, mp 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[Br:16]Br>C1COCC1>[Br:16][C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1
Reactant: BrBr
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(Br)sc12
Reaction time: 0.5 h
Yield: 755.8 %

Procedure:
To a stirred solution of 2 (10.12 g, 5.59 mmol) in dry THF (200 ml) at −78° C. was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 15 minutes. Bromine (18.9 g, 120 mmol) was added slowly and the reaction mixture was stirred for additional 30 minutes, quenched with water and diluted with EtOAc. The organic phase was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (eluent EtOAc/Hexane 9:1) afforded title compound 49 (10.5 g, 71% yield) as a yellow solid. 1H NMR (CDCl3) δ (ppm): 8.62 (d, J=5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=5.09 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].Cl.[F:40][C:41]1[CH:49]=CC=[C:46]2[C:42]=1CN[CH2:45]2.Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:14](=[O:26])[NH:15][C@:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]2[CH:19]=[CH2:20])[CH2:10][C@@H:11]([O:13][C:27]([N:34]2[CH2:35][C:49]3[C:37](=[CH:45][CH:46]=[CH:42][C:41]=3[F:40])[CH2:38]2)=[O:28])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Fc1cccc2c1CNC2
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
8.19 g of crude (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 60 mL of toluene and 4.25 g carbonyldiimidazole (26.2 mmol) was added in portions at a temperature of 22° C. to 25° C. The reaction mixture was stirred for 1.5 h at ambient temperature. Then 3.66 g (21.0 mmol) of 4-fluoroisoindoline hydrochloride was added in portions followed by 3.1 mL of triethylamine. The resulting suspension was heated to 52° C. bath temperature. After stirring for 3 h at this temperature the reaction mixture was cooled with an ice bath and 70 mL of aqueous HCl (1M) were added. The mixture was extracted with 50 mL of toluene. The separated aqueous layer was extracted twice with 50 mL toluene. The combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of sodium carbonate (5% w/w). The toluene extract was dried with sodium sulfate, filtered, and the solvent was completely removed to afford 9.21 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as a grey solid, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 5 ml of benzene. To the obtained solution, 0.61 ml of acetic anhydride was added and the resultant solution was refluxed for one hour. After distilling off benzene, the obtained crude product was washed with hexane to obtain 3-(5-acetylamino-4-chloro-2 fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H) -pyrimidinedione as white crystals.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]>C(O)C>[CH3:4][NH:6][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)N1N=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2CC1C)OCO3
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNCC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 38.4 %

Procedure:
1.31 g (19.5 mmol) of methylamine hydrochloride and 2.24 ml (23.3 mmol) of triethylamine were added to a suspension containing 1.61 g (3.89 mmol) of 1-(4-chloroacetylamino-phenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 106) in 100 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was purified by column chromatography (adsorbent: Kieselgel 60, eluent: chloroform--methanol 9:1). The crude product was triturated with 3 ml of 50% ethanol at 25° C. to give 0.61 g (38.6%) of the aimed product, m.p.: 220°-222° C. (weak decomp.).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CN([P+](O[N:44]2N=[N:51][C:46]3C=[CH:48][CH:49]=[CH:50][C:45]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N[C:61]1C=NC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:44][C:45]4[CH:46]=[N:51][CH:48]=[CH:49][CH:50]=4)=[O:24])=[C:25]([CH3:61])[CH:26]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: Nc1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)ccc1C(=O)Nc1cccnc1

Procedure:
Stir a mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.188 g, 0.50 mmol), PyBOP (0.0.288 g, 0.50 m mol), and 3-amino-pyridine (0.063 g, 0.59 mmol) in dry CH2Cl2 (10 mL) under N2 add Hunigs base (0.148 g, 0.200 mL, 1.11 mmol). Stir overnight the reaction at ambient temperature and evaporate on the rotary evaporator. Chromatograph the residue on the ISCO using a 40 g column and a hexane-EtOAc gradient system (0-100%) to give 0.048 g of the title compound as a white foam. Mass spectrum (m/e) (M+H) 460.1697; found 460.1681.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][CH:24]=[CH2:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon, was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred for 1 hour, then 1.07 ml of allyl bromide was added. The mixture was stirred overnight, then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed as described in Example 1. The active fractions were combined, evaporated and the solid recrystallized from ethyl acetate-hexane, giving 1.46 g of the desired product as tan crystals, mp 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4C(F)(F)F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(N(C(C)C)CC)(C)C.CN(C([O:28][N:29]1[N:37]=[N:36][C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>CN(C=O)C.C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][O:28][N:29]2[C:30]3=[N:35][CH:34]=[CH:33][CH:32]=[C:31]3[N:36]=[N:37]2)[CH:4]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(CBr)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(COn3nnc4cccnc43)c2)c1
Reaction time: 0.08 h

Procedure:
To 3-(bromomethyl)benzoic acid (200 mg, 0.93 mmol) and diisopropylethylamine (566 μL, 3.26 mmol) in DMF (5 mL) is added HATU (424 mg, 1.12 mmol), and the reaction is stirred 5 min. To the reaction is added (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in EXAMPLE SP-272 (379 mg, 0.93 mmol), and the reaction stirred 30 min. The reaction mixture is diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine. The organic layer is then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound. ESI MS m/z 587.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH-].[NH4+:16]>>[OH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:16])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Oc1ncc(Br)nc1N1CCOCC1
Agent: [OH-]
Product: Nc1cnc(O)c(N2CCOCC2)n1

Procedure:
A mixture of 2-hydroxy-3-morpholino-5-bromopyrazine (1g.) in 100 ml. of concentrated ammonium hydroxide is heated overnight at 100°-140° C. in a sealed tube to give 2-hydroxy-3-morpholino-5-aminopyrazine.
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]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[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]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1ccc2ccccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccc2ccccc2c1
Yield: 78.5 %

Procedure:
105 g (0.48 mol) of 25 and 90 g (0.5 mol) of N-bromo-succinimide were dissolved in 2000 cm3 of tetrachloromethane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 112 g (79%) of 26 as a colorless lachrymatory oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[OH:25][CH:24]([C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:27][CH:26]=1)[C:10]1[S:11][C:5]2[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3ccc([N+](=O)[O-])cc3)sc21

Procedure:
Prepared from 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Example 51, step c) and 4-nitrobenzaldehyde following the method of Example 51, step d.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][NH:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:18]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=[CH:20][C:21]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][NH:12][C:13](=[O:17])[NH:14]4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1NCc2ccc(N3CCNCC3)cc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NCc2ccc(N3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Representative procedure: To a solution of compound 5 (0.15 g, 0.43 mmol) and biphenyl-4-carbaldehyde (a) (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0° C. was added Et3N (0.13 mL, 0.97 mmol). After being stirred for 0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol) was added, and the mixture was stirred for 6 h. Sat. NaHCO3 solution (5 mL) was added and stirred for 15 min, followed by the addition of ethyl acetate (20 mL). The organic layer was separated and washed with sat. NaHCO3, brine, and dried over Na2SO4 and evaporated. Column chromatography on silica gel, eluting with methanol:dichloromethane (5:95) and then changing to 10:90 afforded 0.099 g (58%) of compound 5a as an off-white solid, m.p. 134-135° C.; IR (KBr) νmax. cm−1: 3431 (NH), 3062 (Ar—H), 2963 (Alph-H), 1703 (C═O), 1620, 1512, 1430 (C═C), 1221 (C—N), 1168 (C—O). 1H NMR (500 MHz, DMSO-d6) δ=2.71 (m, 4H, 2CH2); 3.14 (m, 4H, 2CH2); 3.68 (s, 2H, CH2); 4.47 (s, 2H, CH2); 6.64 (d, 1H, J=2.3 Hz, aromatic H); 6.68 (d, 1H, J=8.3 Hz, aromatic H); 6.78 (dd, 1H, J=2.2, 8.4 Hz, aromatic H); 7.43-7.48 (m, 5H, aromatic H); 7.58-7.61 (m, 4H, aromatic H); 13C NMR (125.7 MHz, DMSO-d6) δ=43.78 (CH2), 50.11 (CH2), 53.02 (CH2), 62.69 (CH2), 98.21 (aromatic-C), 114.64 (aromatic-C), 115.15 (aromatic-C), 117.28 (aromatic-C), 118.25 (aromatic-C), 127.18 (aromatic-C), 127.28 (aromatic-C), 127.53 (aromatic-C), 127.91 (aromatic-C), 128.97 (aromatic-C), 129.21 (aromatic-C), 130.29 (aromatic-C), 130.57 (aromatic-C), 140.92 (aromatic-C), 147.12 (aromatic-C), 156.34 (C═O). Calculated (%) for C25H26N4O (398.21); C: 75.35, H: 6.58, N: 14.06. found (%); C: 75.28, H: 6.64, N: 13.97.
Reaction SMILES: [Na].[C:2]([C:5]1[N:10]=[C:9]([P:11](=[O:30])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[N:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:8]=[CH:7][CH:6]=1)([OH:4])=[O:3].C([O-])(=O)C.[Gd+3:35].C([O-])(=O)C.C([O-])(=O)C>O>[Gd:35].[C:27]([C:23]1[N:22]=[C:21]([P:11](=[O:30])([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([OH:4])=[O:3])[N:10]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: [Gd+3]
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(P(=O)(c2cccc(C(=O)O)n2)c2cccc(C(=O)O)n2)n1
Agent: [Na]
Solvent: O
Product: [Gd]
Temperature: 90 °C

Procedure:
A reaction flask was equipped with a reflux condenser, agitator, addition finnel, nitrogen source and heating bath. The tris(6-carboxy-2-pyridyl)phosphine oxide sodium salt (310 mg, 0.65 mmol, MW 479) from Example 11 was dissolved warm demineralized water (10 mL) and the resultant solution was filtered and charged to reaction flask. Gadolinium (III) acetate (250 mg, 0.62 mmol, MW 406 for tetrahydrate) was dissolved in warm demineralized water (10 mL) and the resultant solution was filtered and charged to the addition funnel. The bath was heated to 90° C. and the gadolinium acetate solution was added dropwise with agitation over 30 min. Once the addition was complete, the reaction was cooled to ambient temperature and the white solids were isolated by filtration and washed with demineralized water. The solids were dried in vacuo to afford 100 mg of white solids (367 mg theoretical yield for anhydrous complex), and which following structural formula: ##STR15##
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])C.Cl.FC1C=C(C=CC=1)COC1C=CC2CC[NH:42]CCC=2C=1.C(C(C(Cl)=O)C(Cl)=O)C>C(N(CC)CC)C>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([NH2:42])=[O:3])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CCOC(=O)CC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)CC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 70 %

Procedure:
3-[7-(3-Fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-3-oxo-propionic acid ethyl ester: The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and ethyl malonic acid chloride with triethylamine as the base. Yield: 70% of theory as a colourless oil; MS: m/e=386 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]=[CH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:12](O)C.Cl.[CH2:16]([NH:23][OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C=O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH:10]1[O:24][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: ONCc1ccccc1
Reactant: CCO
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following the procedure described in Tetrahedron 55, 1999, 4685-4698, N—BOC-allylamine (2 g) was dissolved in toluene (130 ml) and ethanol (45 ml) then benzylhydroxylamine hydrochloride (3.05 g), paraformaldehyde (3.16 g) and triethylamine (1.93 g) were added. The reaction mixture was allowed to stir at room temperature for 24 hours, then the solvent was evaporated in vacuo. The resulting residue was diluted in ethyl acetate and the hydrochloride salt of triethylamine was filtered off. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a colorless oil (4.37 g). LCMS (Method F) 1.53 min, M+H 293.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23](O)=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[ClH:61].[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C.CC(=O)OCC>[OH:74][B:69]1[C:68]2[CH:75]=[C:64]([CH2:63][NH:62][C:23]([C:17]3[N:18]4[C:22]([C:14]([C:11]5[CH2:10][C:9]([C:4]6[CH:3]=[C:2]([Cl:1])[C:7]([Cl:61])=[C:6]([Cl:8])[CH:5]=6)([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=5)=[CH:15][CH:16]=3)=[CH:21][CH:20]=[CH:19]4)=[O:24])[CH:65]=[CH:66][C:67]=2[C:71]([CH3:73])([CH3:72])[O:70]1
Reactant: Cl
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)c4cccn34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a solution of compound 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (80 mg, 0.168 mmol), HATU (96 mg, 0.252 mmol) and Et3N (0.08 mL, 0.504 mmol) in DMF (15 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-olhydrochloride (40 mg, 0.168 mmol). The mixture was stirred at rt overnight. EA (50 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxamide (54 mg, yield 61%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (t, J=6.0 Hz, 1H), 9.04 (s, 1H), 8.18 (s, 1H), 7.89 (s, 2H), 7.68 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.19 (m, 2H), 7.11 (d, J=2.8 Hz,1H), 6.94 (t, J=2.8 Hz,1H), 4.57 (d, J=5.6 Hz, 2H), 4.48 (d, J=18.0 Hz, 1H), 4.41 (d, J=18.0 Hz, 1H), 1.44 (s, 6H) ppm; HPLC purity: 99.64% at 220 nm and 100.0% at 254 nm; MS: m/z=649.7 (M+1, ESI+).