Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([NH:11]N=C2CCCNC2=O)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:20]([OH:23])(=O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[O:8][CH2:7][CH2:6][C:5]2=[C:9]2[C:10]=1[NH:11][C:21]1[C:20](=[O:23])[NH:11][CH2:10][CH2:9][C:5]2=1
Reactant: O=C1NCCCC1=NNc1cc2c(cc1Br)OCC2
Reactant: CC(=O)O
Product: O=C1NCCc2c1[nH]c1c(Br)cc3c(c21)CCO3
Temperature: 115 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[(6-bromo-2,3-dihydro-1-benzofuran-5-yl)hydrazinylidene]piperidin-2-one (a mixture of E and Z isomers)(137 mg) and acetic acid (3.00 mL) was stirred at 115° C. for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 96:4) to obtain 5-bromo-1,2,6,8,9,10-hexahydro-7H-furo[3,2-e]pyrido[3,4-b]indol-7-one (40.0 mg) as a red solid.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(=O)(O)[O-].[Na+].Cl[C:10]1[CH:11]=[C:12]([C:19]2[C:24]3[N:25]([CH2:37][C@H:38]4[CH2:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39]4)[C:26]([N:28]4[CH2:33][CH2:32][O:31][C@@H:30]5[CH2:34][CH2:35][CH2:36][C@@H:29]45)=[N:27][C:23]=3[CH:22]=[C:21]([C:45]#[N:46])[N:20]=2)[C:13]([N:16]([CH3:18])[CH3:17])=[N:14][CH:15]=1>O.C(O)C>[Cl:1][C:10]1[CH:11]=[C:12]([C:19]2[C:24]3[N:25]([CH2:37][C@H:38]4[CH2:39][CH2:40][C@H:41]([CH3:44])[CH2:42][CH2:43]4)[C:26]([N:28]4[CH2:33][CH2:32][O:31][C@@H:30]5[CH2:34][CH2:35][CH2:36][C@@H:29]45)=[N:27][C:23]=3[CH:22]=[C:21]([C:45](=[NH:46])[NH:2][OH:3])[N:20]=2)[C:13]([N:16]([CH3:17])[CH3:18])=[N:14][CH:15]=1
Reactant: CN(C)c1ncc(Cl)cc1-c1nc(C#N)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Reactant: NO
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)c1ncc(Cl)cc1-c1nc(C(=N)NO)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydroxylamine hydrochloride (4.3 mg, 0.07 mmol) and sodium bicarbonate (7 mg, 0.08 mmol) were dissolved in water (0.4 mL) and stirred at room temperature for 10 minutes, allowing gas to evolve. This solution was then added to a solution of 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (racemic, 26 mg, 0.05 mmol) in ethanol (0.2 mL). This reaction mixture was stirred at 90° C. for 1 hour. The reaction mixture was concentrated and diluted with water (2 mL). The solid was filtered off to afford (crude) 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (racemic). MS ES calc'd. for C29H39ClN8O2 [M+H]+ 567. found 567.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C#N)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (25 mL) was added dropwise 4-cyanobenzoyl chloride (92 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D -47° (c 1.0, CHCL3); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH:9]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24]/[CH:25]=[CH:26]/[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)[CH2:20][CH2:19]3)[C:8]=2[CH:53]=1)([O-:3])=[O:2]>C(O)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH:9]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24]/[CH:25]=[CH:26]/[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=4)[CH2:22][CH2:23]3)[C:8]=2[CH:53]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(N1CCN(C/C=C/c3cccc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CC1)c1ccccc1CC2
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(/C=C/CN2CCN(C3c4ccccc4CCc4ccc([N+](=O)[O-])cc43)CC2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
7.0 g of 3-nitro-5-[4-{(E)-3-(3-triphenylmethylaminophenyl)allyl}piperazin-1-yl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene was dissolved in 20 ml of acetic acid and 20 ml of methanol. The solution was stirred for 2 hours at 40° C. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous sodium hydrogen-carbonate solution, water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: chloroform/ethanol=50/1) to obtain 3.77 g of light yellow solid 3-nitro-5-[4-{(E)-3-(3-aminophenyl)allyl}-piperazin-1-yl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:16][C@:8]2([C:13]([CH3:15])([CH3:14])[C:9]32[CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]1[C:17](=[O:45])[C@@H:18]([NH:23][C:24](=[O:44])[C@H:25]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]([CH3:37])[CH3:36])=[O:28])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:4]>C1COCC1.CO.O>[CH:38]1([C@H:25]([NH:26][C:27]([C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[CH:35]([CH3:37])[CH3:36])=[O:28])[C:24]([NH:23][C@@H:18]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:17]([N:6]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:16][C@:8]3([C:13]([CH3:14])([CH3:15])[C:9]43[CH2:12][CH2:11][CH2:10]4)[CH2:7]2)=[O:45])=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCCN1C(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)N1CCCC[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N1C[C@]2(C[C@H]1C(=O)O)C(C)(C)C21CCC1)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5R,8S)-7-((S)-2-{(S)-2-Cyclohexyl-2-[((S)-1-isopropyl-piperidine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (0.69 g; 1.10 mmol) in THF/Methanol/water (2:1:1; 20 mL) was added LiOH monohydrate (0.138 g; 3.3 mmol) and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo, water was added, the product was frozen in liquid nitrogen and lyophilized overnight to yield the title compound. LC-MS (method E): Rt=1.50 min; M/z=615 [M+]; HPLC (method A3): Rt=4.38 min
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([O:13][C:15](=[O:17])[CH3:16])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 22 °C
Reaction time: 10 h
Yield: 79.4 %

Procedure:
To a stirred solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e, 13.5 g, 67 mmol), TEA (81 g, 804 mmol), DMAP (1.6 g, 13 mmol) in anhydrous DCM (150 mL) was added acetic anhydride (62 g, 603 mmol). After being stirred at 22° C. for 10 hours, the reaction was quenched by the saturated NaHCO3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 EtOAc in petroleum ether) to afford 13 g of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl]acetate (compound 6f) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH3:24])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33]>CO.[OH-].[Na+]>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH3:24])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([C:35]([F:37])([F:38])[F:36])(=[O:34])=[O:33]
Reactant: CCOC(=O)c1c(Cl)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc(Cl)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Yield: 91.5 %

Procedure:
A solution of product of Example 95 (0.4 g) in methanol (20 ml) and 2M NaOH (4 ml) was heated at reflux for 1.5 h. The solution was concentrated in vacuo. It was then diluted with water (10 ml) and extracted with diethyl ether (10 ml). The aqueous layer was acidified to pH5 with 2N HCl and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (0.35 g) as a pale beige solid, m.p. 109°-110° (dec.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(Br)ccc2n1
Yield: 42 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-bromopyridine instead of 2-aminopyridine, to the title compound (75 mg, 42%) which was obtained as a yellow gum. MS: m/e=354.1/356.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: NCCCNc1nsc2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (1.20 g, 5.77 mmol), 4′-methoxybiphenyl-4-carbaldehyde (1.22 g, 5.77 mmol), sodium triacetoxyborohydride (2.50 g, 11.8 mmol) and acetic acid (one drop) was taken up in methylene chloride (25 mL) and stirred overnight at room temperature under argon. The crude reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 95:5 methylene chloride:methanol yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine. 1H NMR (300 MHz, CD3OD): 8.66-8.68 (d, 1H), 8.40-8.45 (d, 1H), 7.33-7.45 (m, 7H), 6.96 (s, 1H), 6.93 (s, 3.83 (s, 2H), 3.80 (s, 3H), 3.58-3.63 (t, 2H), 2.78-2.83 (t, 2H), 1.96-2.00 ppm (t, 2H). MW=405 confirmed by LC-MS, tr=9.08 min (Method Y) MH+=406.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:14]([CH2:16][CH2:17][CH:18](Br)[CH3:19])[CH3:15]>C(O)C>[CH3:19][CH:18]1[CH2:17][CH2:16][CH:14]([CH3:15])[C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(Br)CCC(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(C)CCC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Sodium metal (16 g, 0.7 mole) was dissolved in absolute ethanol (500 ml) under argon with cooling as necessary to maintain a temperature of <70° C. The solution was cooled and redistilled diethyl malonate (54.3 g, 0.362 mole) was added dropwise, with cooling as necessary, followed by 2,5-dibromohexane (85 g, 0.348 mole) in a single portion. The reaction mixture was stirred overnight at room temperature and then refluxed for 2 hours. The mixture was then concentrated to approximately half the volume under reduced pressure, water (500 ml) added and the mixture extracted with ether (3×200 ml). The combined extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was fractionated in vacuo to yield diethyl 2,5-dimethylcyclopentane-1,1-dicarboxylate (35 g), which was homogeneous by GC.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>C(O)(C)C>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC(C)O
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
a procedure wherein amorphous maltose beads are refluxed in either anhydrous maltose or anhydrous isopropanol overnight to obtain a crystalline alpha-maltose.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16]([NH:18][CH:19](P(OC)(OC)=O)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].O.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6](/[CH:7]=[C:19](\[NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])/[C:20]([O:22][CH3:23])=[O:21])[CH:9]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1cc(Br)ccc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
21.32 ml (169.9 mmol) of N,N,N,N-tetramethylguanidine are added to a solution, cooled to −70° C., of 30 g (147.8 mmol) of 5-bromo-2-fluorobenzaldehyde and 50.51 g (169.9 mmol) of methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate in 450 ml anhydrous tetrahydrofuran. After stirring at −70° C. for 4 h, the reaction mixture is stirred at RT for 15 h. 1000 ml of water and 1000 ml of ethyl acetate are added to the mixture. The organic phase is washed with water, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 4:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=O>C(#N)C>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1
Reactant: O=C(CBr)c1cccs1
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Solvent: CC#N
Product: O=C(Nc1ccc2nc(-c3cccs3)cn2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 100 %

Procedure:
Compound 6 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.126 g of the expected product is thus obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 111.8 %

Procedure:
5-bromo-2-fluoronitrobenzene (5.0 g, 22.7 mmol), 2-(methylamino)ethanol (4.26 g, 56.8 mmol) and K2CO3 (9.4 g, 68.1 mmol) in DMF (20 mL) was heated to 60° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.98 g (100%) of the desired product 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethanol (25B): 1H NMR (300 MHz, CDCl3) δ 7.87 (1H, d), 7.51 (1H, dd), 7.10 (1H, d), 3.77 (2H, t), 3.39 (2H, t), 2.83 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: COc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(Cl)cc1
Yield: 95 %

Procedure:
2-Bromoanisole (97 mg, 0.52 mmol) reacted with 4-chlorophenylboronic acid (102 mg, 0.65 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (8.8 mg, 1.57 mmol) in THF (2 ml) at room temperature to give the title compound (108 mg, 95%): 1H-NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, J=8.0 Hz), 7.46-7.32 (m, 2H), 7.08 (t, 1H, J=7.6 Hz, aryl coupling J=1.2), 7.03 (d, 1H, J=8.0 Hz), 3.85 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.27, 136.86, 132.79, 130.81, 130.60, 129.33, 128.94, 128.10, 120.85, 111.16, 55.47. GC/MS(EI): m/z 218 (M+), 220 (M++2, Cl isotope peak), 168, 139. Anal. Calcd for C13H11ClO: C, 71.40; H, 5.07. Found: C, 71.47; H, 5.21.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7]I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][CH:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30](CC=C)[C:31]([NH:33]CC2C=C(F)C=C(F)C=2)=[O:32])[C:11]1=[O:51].C([O-])(=O)CCC([O-])=O.CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(N)C1=O>>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][C@H:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30]([CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:31]([NH2:33])=[O:32])[C:11]1=[O:51]
Reactant: C=CC[C@H](C(=O)NCc1cc(F)cc(F)c1)[C@@H](CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: ICCC1CCCC1
Agent: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])CCC(=O)[O-]
Product: CC(C)C[C@@H](C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O)[C@H](CCC1CCCC1)C(N)=O

Procedure:
A procedure analogous to the preparation of Example 5 was followed. The appropriate succinate ester was prepared using the method disclosed in PCT publication WO 98/51665, using 2-(cyclopentyl)ethyl iodide for R3—X in place of allyl bromide (see Scheme 2). The anti-succinate half-ester was coupled to (S)-isomer benzodiazepine (30) using the procedures of Step 1. After Steps 2 and 3, the title compound was isolated. MS (M+H)=475; (M+Na)+=497.2.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1C
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(C)c(C)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3,4-dimethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=405.12.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:1].[ClH:1].[CH2:14]([C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:8]=2)=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:11]=1)[CH3:15]
Reactant: C1CCNC1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CCl)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CN3CCCC3)c2)s1
Product: Cl
Yield: 85 %

Procedure:
To a solution of 5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole (0.20 g, 0.61 mmol) in pyrrolidine (0.5 mL) was stirred for 1 hour at 80° C. After cooling, to this was added an aqueous potassium carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, then, dried and concentrated. The residue was purified by alumina column chromatography (hexane-ethyl acetate=2:1). The resulting oil was made into a hydrochloride by using a solution of 4N-hydrogen chloride in ethyl acetate, and recrystallized from ethanol-isopropyl ether, to obtain a title compound (0.23 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1>[C:16]1([C:2]2[CH:15]=[CH:14][C:13]3[C:4](=[CH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Reactant: OB(O)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Into a flask, 5.00 g of 2-chloroanthracene, 4.3 g of phenylboronic acid, 538 mg of tris(dibenzylieneacetone)dipalladium(0), 494 mg of tricyclohexyl phosphine, 9.98 g of tripotassium phosphate, and 75 ml of toluene were put, and the solution was stirred at reflux temperature for 2 hours under argon atmosphere. After heating, 1.5 liter of toluene was added to the reaction liquid, the liquid was cooled to room temperature and then filtrated, and thus the filtrates were purified by silica gel column chromatography. The filtrates were concentrated in an evaporator, the concentrates were recrystallized in toluene, and thus 5.0 g of 2-phenylanthracene was obtained.