Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:37][CH:38]1[CH:45]2[CH2:46][C:41]3([OH:48])[CH2:42][CH:43]([CH2:47][CH:39]1[CH2:40]3)[CH2:44]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:48][C:41]12[CH2:46][CH:45]3[CH2:44][CH:43]([CH2:47][CH:39]([CH:38]3[NH:37][C:15]([C:13]3[CH:12]=[CH:11][C:10]4[N:6]([CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:7]=[N:8][C:9]=4[CH:14]=3)=[O:17])[CH2:40]1)[CH2:42]2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.65 g, 0.0028 mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g, 0.0034 mol), DIPEA (2.5 mL, 0.014 mol), 4-aminoadamantan-1-ol (0.685 g, 0.0034 mol) at 0° C. To the resulting mixture was added EDCl (0.65 g, 0.0034 mol) and stirred for 15 h at ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated affording (1.0 g, 93.5%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide. MS-ESI m/z 381 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:2]1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:2]1
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccccc23)cc1
Reaction time: 0.25 h

Procedure:
A solution of methyl 4-((1H-indol-3-yl)methyl)benzoate (0.250 g, 0.94 mmol) in THF is added dropwise to a suspension of NaH (0.048 g, 1.19 mmol) in THF. The mixture is stirred for 15 minutes, treated with methyl iodide (0.154 g, 1.08 mmol), stirred for 30 minutes and concentrated in vacuo. The resultant solid residue is partioned between CH2Cl2 and H2O. The organic phase is separated, dried over Na2SO4 and concentrated to dryness to yield methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH3:19].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH2:16])[CH2:19][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C#N)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-cyano-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (1.2 g, 5.1 mmol) in THF (100 mL) was added ethylmagnesium bromide (3 M, 3.3 mL, 10 mmol) and titanium isopropoxide (2.3 mL, 7.7 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added (5 mL) and the resulting solids filtered off. The organics were concentrated, then purified by flash chromatography on silica gel using 5-10% MeOH/CH2Cl2 to afford [2-(1-amino-cyclopropyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester as a solid, m/z 264.4 [M+1]+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:18])[CH3:16])[NH:13][C:12]1=[O:29])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[O:18])[CH3:16])[N:13]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[C:12]1=[O:29])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(COC(=O)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N2CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-p-methoxybenzyloxycarbonylethyl]azetidin-2-one (1.12 g) in methylene chloride (14 ml), there were successively added p-nitrobenzyl alpha-bromoacetate (1.09 g), 50% aqueous sodium hydroxide solution (0.85 g) and triethylbenzylammonium chloride (303 mg), followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with a mixture of diethyl ether and methylene chloride (3:1) three times. The organic layer was washed successively with water two times and brine three times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-p-methoxybenzyloxycarbonylethyl]-1-(p-nitrobenzyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: C([S-])C.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15]C)[CH:14]=1)[CH:10]=[O:11].[Cl-].[Na+].C=O>CN(C=O)C.C(O)(=O)C>[OH:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][CH3:5])[CH:14]=1)[CH:10]=[O:11]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: C=O
Agent: CC[S-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(O)cc(C=O)c1
Temperature: 145 °C
Reaction time: 1 h

Procedure:
To a 1.0-L three-neck flask was added sodium ethanethiolate (80%, 28.5 g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145° C. for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of 8 minutes. The reaction was kept at 145° C. for another 1 hour, then cooled to room temperature. Saturated sodium chloride solution (2.5 L) and formaline (37%, 240 mL) together with acetic acid (500 mL) was added. The resulting solution was thoroughly extracted with ethyl acetate, the organic phase was dried with sodium sulfate, and the solvent was removed under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1) to give 3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[CH:25]2[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]2)[NH:32][C:31]1=[O:37]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 42.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (34 mg, 42.9%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:12][C:11]1[CH:38]=[CH:39][CH:40]=[CH:41][C:10]2=1)=[O:5])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH2:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:12][C:11]1[CH:38]=[CH:39][CH:40]=[CH:41][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (100 mg, 0.174 mmol) in DCM (5 mL), was added trifluoroacetic acid (0.52 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 5-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (80 mg, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Yield: 96 %

Procedure:
4-(5-Nitropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.08 g, 10 mmol) was treated with 15% TFA in dichloromethane (50 mL) at 25° C. for 1 h. The solution was concentrated in vacuo to provide 1-(5-nitropyridin-2-yl)piperazine as a brown solid (2.0 g, 96% yield over two steps). MS (ES+) m/z 209.4 (M+1).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:59])[N:46](CCN(C1C=CC=C(N)C=1)C)[CH3:47])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:59])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(CCN(C)c1cccc(N)c1)C(=O)OC(C)(C)C
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that {2-[(3-amino-phenyl)-methyl-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (prepared in three steps from 3-fluoro-1-nitrobenzene and N,N′-dimethylethylenediamine) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.09 (1H, s), 7.50-7.45 (2H, m), 7.29-7.24 (1H, m), 7.12-7.01 (3H, m), 6.53-6.46 (2H, m), 4.69-4.67 (2H, m), 4.38 (1H, d, 13.8), 4.17 (1H, d, 13.8), 3.50-3.44 (2H, m), 2.93 (3H, s), 2.86-2.74 (3H, m), 2.49 (3H, s), 2.04-1.58 (7H, m), 1.31-1.19 (13H, m). Found: C, 65.52; H, 7.53; N, 14.12%; C32H44N6O5.0.4CH2Cl2 requires: C, 65.58; H, 7.61; N, 14.17%.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([NH:42]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([NH2:42])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6) (47.3 mg, 0.133 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (41.0 mg, 0.118 mmol) and HATU (142.3 mg, 0.3742 mmol), DMF (2.0 mL) was added followed by DIPEA (115.8 mg, 0.8960 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25.2 mg, 44%). LCMS calc. for C23H25F2N6O2S (M+H)+: m/z=487.2. found 487.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CC(C)N[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and isopropylamine. Melting point: 61°-63° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:20])[CH:18]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:8](=[CH:16][CH:17]([CH3:20])[CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC(C)C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC(C)C)Cc1ccc(F)cc1

Procedure:
A solution of 210 g (1 mmol) of ethyl 4-fluorobenzoylacetate and 144 g (2 mol) of 2-methylpropanal are stirred overnight at 50° C. with 7 ml of piperidine and 5 ml of acetic acid in 100 ml of isopropanol. After reaction is complete, the batch is concentrated at about 15 Torr and the crude product (270 g, about 85%) is reacted without further purification.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].Cl.C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>C1(C)C=CC=CC=1>[NH:25]1[C:1]([CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:2][N:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnn[nH]2)CC1
Temperature: 80 °C

Procedure:
To a stirred suspension of 1.50 g (6.66 mmol) of the title compound from Step A above in 25 mL of anhydrous toluene was added 1.38 g (10.0 mol) of triethylamine hydrochloride followed by 0.65 g (10 mmol) of sodium azide. The resoling mixture was heated to 80° C. for 12 h then cooled to ambient temperature. All volatiles were removed in vacuo, and the residue suspended in 5 mL of brine and 1.0 N aqueous hydrogen chloride solution was added until pH of ˜4 was achieved. The aqueous phase was extracted with chloroform and the combined organics were dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% acetone in hexanes gradient to afford the title compound (i-105) as white solid (1.1 g, 63%). 1H-NMR (500 MHz, DMSO-d6) δ 3.82 (s, 2H), 3.29 (br s, 4H), 2.38-2.34 (m, 4H), 1.36 (s, 9H). LC-MS: m/z (ES) 269.0 (MH)+.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[CH:12]=1)[CH3:8])(=O)C>CO.O>[O:24]=[C:14]1[C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][CH:7]([OH:6])[CH3:8])[CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: CC(=O)OC(C)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Yield: 95.2 %

Procedure:
Sodium hydroxide (0.2 gram) was dissolved in a mixture of 20 ml of methanol and 5 ml of water, then 1.47 grams of 4-(9-oxo-2-fluorenyl)-butan-2-ol acetate was added thereto, and the mixture was heated to reflux for two hours. After removal of methanol by evaporation therefrom, chloroform was added to the residue, the mixture was washed with water, and dried with magnesium sulfate. Chlorform was evaporated therefrom and the residue was allowed to stand to give crystals. They were recrystallized from isopropyl ether to give 1.2 grams of 4-(9-oxo-2-fluorenyl)-butan-2-ol, yellow crystals, m.p. 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(c1c(Cl)cccc1Cl)C2=O
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(Cl)cccc2Cl)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (403 mg), EDCI (121 mg) and HOBt (135 mg) in DMF (8 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue crystallized from EtOAc to give 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=238-240° C.; MS (m/z) 439 (M−1); 1H NMR DMSO-d6, 400 MHz) δ 10.49 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=7.83 Hz, 1H), 8.24 (d, J=7.58 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.67 (t, 1H), 7.59 (s, 1H), 7.53 (d, J=8.08 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N+:9]([O-])=O)[S:5][CH:6]=1.[Li+].[BH4-].Cl[Si](C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1
Reactant: O=[N+]([O-])C=Cc1cc(Br)cs1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cc(Br)cs1
Yield: 99.9 %

Procedure:
Using analogous reaction conditions and workup as described in Example 14, step 2, 4-bromo-2-(2-nitro-vinyl)-thiophene (5 g, 21.367 mmol) in dry THF (150 mL) was reacted with LiBH4 (1.86 g, 85.470 mmol), chloro trimethyl silane (21.6 mL, 170.576 mmol) to afford 4.4 g of the crude product which was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][OH:55]>CN(C)C=O>[OH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: OCCOCCOCCCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CCOCCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide (1 ml). Sodium iodide (7.5 mg, 0.5 mmol) , triethylamine (76 mg, 0.75 mmol) and 2-[2-(2-chloroethoxy)-ethoxy]ethanol (85 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred at ambient temperature for 90 minutes, the temperature was then raised to 100° C. and kept there for 1 hour. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was acidified, the water was evaporated and the title compound was isolated as a hygroscopic white powder. Yield 77 mg (64%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)=[O:4]>CO.C1COCC1>[OH:4][CH2:3][C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1
Reactant: CN(C)C(=O)c1cc2cc(C=O)cnc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc2cc(CO)cnc2o1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (6.0 g, 0.16 mol) was added to a solution of 5-formyl-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (6.9 g, 0.032 mol) in methanol (80 mL) and THF (20 mL) at 0° C., and the resulting mixture was gradually warmed to 23° C. and stirred for 1 h. The excess of sodium borohydride was carefully quenched with water. The reaction mixture was concentrated, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 70% ethyl acetate in petroleum ether to give the title compound. MS: m/z=221.0 (M+1).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[C@@H:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[OH:25]
Reactant: CCCCCC
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5 mL, 3.0 mmol) was added to a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then, the ice bath was removed and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (533 mg, 100%).