Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9](O)[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCC(O)c2sccc21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCC=Cc2sccc21
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of 0.90 g of 4-(2-chloro-4-nitrobenzoyl)-8-hydroxy-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 5 ml of dichloromethane cooled to -10° C. is added under argon 533 μl of triethylamine and dropwise 296 μl of methanesulfonyl chloride. After one hour the cooling bath is removed and the mixture allowed to stand at room temperature overnight. The mixture is diluted with 10 ml of dichloromethane and 5 ml of water. The organic layer is separated, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give an oil which is crystallized by adding hexane. Filtration gives light yellow crystals (0.80 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13]([OH:15])([CH3:23])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC(=O)C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(Br)n2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 114.3 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate (800 mg, 2.17 mmol) in THF (40 mL) at −78° C. was added CH3MgBr (169 mg, 1.44 mmol). The mixture was stirred at −78° C. for 2 hours, quenched with 10% NH4Cl solution (35 mL), extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1˜10:1) as eluting solvents to afford tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (636 mg, 76%). MS (ESI) m/z: 386 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH2:8][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ncc(CBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncc(Cn2ccnc2)cc1Br

Procedure:
Synthesized from 6a (2.38 g, 8.34 mmol), imidazole (1.14 g, 16.7 mmol) and K2CO3 (5.76 g, 41.7 mmol) according to Method B. Yield: 1.88 g, 6.90 mmol, 83%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.14 (s, 2H), 6.89 (bs, 1H), 7.13 (d, J=4.0 Hz, 1H), 7.61-7.63 (m, 1H), 7.70 (brs, 1H), 8.20 (brs, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=46.8, 118.9, 120.8, 130.5, 132.2, 137.2, 140.8, 146.3, 150.9; MS (ESI): m/z=272.05 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:7][C:8]([OH:10])=[O:9])[C:4](O)=[O:5])[CH3:2]>C(Cl)(=O)C>[CH2:1]([C:3]1([CH2:11][CH3:12])[CH2:7][C:8](=[O:10])[O:9][C:4]1=[O:5])[CH3:2]
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Solvent: CC(=O)Cl
Product: CCC1(CC)CC(=O)OC1=O

Procedure:
A mixture of 3.5 g (20 mol) of 2,2-diethylsuccinic acid and 10 ml of acetyl chloride was heated under reflux for 2 hr, cooled, concentrated in vacuo, and reconcentrated three times after the addition of toluene. The residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (126.6 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 5-[5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (107 mg, 58%). 1H NMR (DMSO-d6) δ 2.29 (m, 1H), 2.33 (m, 1H), 2.39 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.37 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.8 Hz, 1H, OH), 6.85 (d, J=8.4 Hz, 1H), 7.11 (dd, J=2.0, 8.0 Hz, 1H), 7.53 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.97 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 457.4 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26])[CH3:23].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:31]3[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=3)[C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)c1
Yield: 63.4 %

Procedure:
To a solution of 2,2-dimethyl-5-trifluoromethanesulfonyloxy-4H-1,3-benzodioxin-4-one (2.0 g, 5.8 mmol), 3-ethoxycarbonylphenylboronic acid (1.34 g, 6.9 mmol) and anhydrous K2CO3 powder (2.61 g, 18.9 mmol) in DMF (30 mL) was added tetrakis(triphenylphosphine)palladium (0.202 g, 0.175 mmol). The mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool to room temperature (“rt”) and 1 N HCl (25 mL) was added. The mixture was extracted with EtOAc (3×25 mL). The combined extracts were washed with water and brine, then dried over MgSO4, filtered, and concentrated. The crude material was purified by flash chromatography (1:15 EtOAc/hexanes) to afford 3-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl)-benzoic acid, ethyl ester (1.2 g, 63%) as a white solid: 1H NMR (CDCl3) 1.39 (t, J=7.1 Hz, 3H), 1.80 (s, 6H), 4.39 (q, J=7.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 7.47-7.57 (m, 3H), 8.00 (t, J=1.5 Hz, 1H), 8.07 (dt, J=7.5, 1.5 Hz, 1H).
Reaction SMILES: [C:1]([CH:3]1[C:8](=[O:9])[CH:7]([CH3:10])[CH2:6][N:5]([C:11]([O:13][CH3:14])=O)[CH2:4]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([OH:29])[CH2:27][OH:28].ClC(Cl)(Cl)C>O>[CH2:26]1[O:29][C:11]([N:5]2[CH2:6][CH:7]([CH3:10])[C:8](=[O:9])[CH:3]([C:1]#[N:2])[CH2:4]2)([O:13][CH3:14])[O:28][CH2:27]1
Reactant: COC(=O)N1CC(C)C(=O)C(C#N)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Product: COC1(N2CC(C)C(=O)C(C#N)C2)OCCO1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of crude 11 (200 g, 1.02 mol), 4-toluenesulfonic acid (35 g), 1,2-ethanediol (900 ml), and 1,1,1-trichlorethane (1 liter) was refluxed with a water separator overnight. The mixture was cooled, water (1 liter) was added and the phases separated. The aqueous phase was extracted 3 times with dichloromethane, and the combined organic phases were washed once with dilute sodium hydroxide solution and once with saturated sodium chloride solution. Drying over magnesium sulphate and evaporation in vacuo of the organic phase yielded 12 (195 g, 80%) as an oil.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16][CH:17]=[CH2:18])(=O)C.[CH3:19][OH:20]>>[OH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH2:16][CH:17]([O:20][CH3:19])[CH3:18]
Reactant: CO
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1OC(C)=O
Product: COC(=O)c1cc(C)c(O)c(CC(C)OC)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of methyl 4-acetoxy-3-allyl-5-methylbenzoate (175 mg, 0.75 mmol) in methanol (2 mL) was cooled in an ice-bath under a nitrogen atmosphere and treated with mercuric trifluoroacetate (322 mg, 1 equivalent). The reaction was stirred in the ice-bath for one hour by which time TLC analysis showed complete consumption of staring material. The reaction was then treated with 1 mL of 3 N NaOH and after vigorous stirring for 2 minutes, a solution of sodium borohydride (0.5 M, 1 mL) in 3 N NaOH was added. The back suspension was stirred for 5 minutes in the ice-bath and then ethyl acetate (25 mL) was added. After stirring for an additional 5 minutes, the ethyl acetate solution was decanted and then washed twice with saturated aqueous ammonium chloride. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product (141 mg, oil) was purified by preparative TLC on silica using 15% ethyl acetate/hexanes. Purified Yield=82 mg (˜50%), MALDI-TOF 239 obs.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22]>CN(C)C=O>[O:16]=[C:7]1[N:6]([CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:11]=2[NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CBr)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CN3C(=O)c4ccccc4Nc4ncccc43)cc2)CCC1
Temperature: 0 °C
Yield: 49.2 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.362 g, 1.05 eq.) was suspended in dimethylformamide (DMF) (5 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (0.2 g, 3.0 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and tert-butyl (1-(4-(2-bromoacetyl)phenyl)cyclobutyl)carbamate (0.6 g, 1.0 eq.) in DMF (1 mL) was added. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of aqueous saturated ammonium chloride solution (1 mL). Dichloromethane was added (15 mL) and the phases were separated. The organic phase was washed with water (3×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (50% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(2-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)acetyl)phenyl)cyclobutyl)carbamate (0.4 g, 50%) as a yellow semi-solid. LCMS: 499 [M+H].
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][CH:14]=3)[C:9](=[O:26])[C:8]=2[C:27]([O-:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClCCl.O>[CH:37]1([NH-:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][CH:14]=3)[C:9](=[O:26])[C:8]=2[C:27]([O-:29])=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCCCC1
Agent: Cl
Agent: O=C([O-])C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: [NH-]C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Phenyl-6-(3-phenylpropyloxy)-1-oxo-1H-indene-2-carboxylate (200 mg, 0.52 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (240 μl, 1.72 mmol) and cyclohexylamine (59 μl, 0.52 mmol) were added thereto at 10° C. Then, after adding bis(2-oxo-3-oxazolidinyl)phosphinic chloride (137 mg, 0.52 mmol), the reaction mixture was stirred for about 20 min at room temperature followed by additional 1 hour at 10° C. After the water was added thereto to complete the reaction, pH was adjusted to 1˜1.5 with 4N hydrochloric acid. The mixture was washed with brine, and extracted with dichloromethane. The extract was dried over anhydrous sulfonate sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:9˜2:8) to obtain the title compound (yield 59.8%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:23]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29](Cl)=[O:30])[CH2:24]1.O>C(Cl)Cl>[CH:25]1([CH2:28][C:29]([N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)=[O:30])[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
5.0 g (0.0246 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 100 ml of CH2Cl2, 4.1 ml (0.0295 mol) of triethylamine were added thereto and a solution of 4.3 ml (0.0295 mol) of 3-cyclopentylacetyl chloride in 40 ml of CH2Cl2 was added dropwise thereto at 15° under argon. The mixture was stirred at room temperature for 1/2 hour, then poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 3:1 there were obtained 6.50 g (84%) of pale yellow oily rac-cis-3-(cyclopentylacetyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:9]=[CH:10][N:11]2[CH2:16][CH:15]([O:17][CH2:18][C:19]([O-:21])=O)[CH2:14][CH2:13][C:12]=12.C(N(CC)CC)C.O.Cl.Cl.[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:50][NH:49][CH2:48][C:46]=2[N:47]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.CN(C)C=O>[CH2:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:50][N:49]([C:19](=[O:21])[CH2:18][O:17][CH:15]3[CH2:16][N:11]4[CH:10]=[CH:9][N:8]=[C:12]4[CH2:13][CH2:14]3)[CH2:48][C:46]=2[N:47]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Reactant: O=C([O-])COC1CCc2nccn2C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COC1CCc2nccn2C1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
Add trifluoroacetic acid (3 mL) to a flask containing tert-butyl 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yloxylacetate (0.30 g; 2.04 equiv; 1.19 mmoles) in dichloromethane (3 mL), and stir at ambient temperature for 1 hour. Concentrate the mixture, add toluene (2×5 mL), and reconcentrate (2×). Add methanol (10 mL) followed by 5 N hydrochloric acid (1 mL), then concentrate. Add toluene (4×5 mL) and reconcentrate (4×). Add dimethylformamide (5 mL), triethylamine (15 equiv; 8.74 mmol; 1.22 mL), N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (0.20 g; 1.0 equiv; 0.583 mmoles) and 1-propanephosphonic acid cyclic anhydride (0.70 mL; 2.0 equiv; 1.17 mmoles) and stir at ambient temperature for 2 hours. Load the solution directly onto a silica gel column and purify by column chromatography (hexanes to ethyl acetate to 20% methanol in ethyl acetate) to give impure product. Further purify the crude product by reverse phase chromatography to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yloxy)ethanone (0.083 g; 33%) as a light yellow foam. MS (m/z): 431(M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1([C:26]([CH3:28])=[CH2:27])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])[C:42](Cl)=[O:43]>C(Cl)Cl.CCOC(C)=O>[F:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])[C:42]([NH:1][CH2:2][CH2:3][CH:4]([C:12]1([C:26]([CH3:28])=[CH2:27])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:43]
Reactant: C=C(C)C1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 137 %

Procedure:
A cold (0° C.) solution of tert-butyl α-(2-aminoethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (1.93 g, 4.99 mmol) in dry CH2Cl2 (20 mL) is treated with diisopropylethylamine (1.04 mL, 5.99 mmol) and 3,4-difluorobenzoyl chloride (691 μL, 5.49 mmol). The solution is allowed to warm to room temperature, stirring under N2 overnight. The solution is diluted with EtOAc (100 mL) and washed with 1N HCl (25 mL), 1N NaOH (25 mL), and brine (25 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 3.60 g of a brown oil. The oil is purified by silica gel chromatography (50 g SG; 25% EtOAc/hexane) to provide 2.10 g (80%) of the title compound as a yellow, amorphous solid:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[C:7]([CH:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[C:7]([C@H:16]3[CH2:17][CH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]3)=[C:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCC(c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2ccc(O)cc2oc(C(F)(F)F)c1[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)cyclohexanecarboxylate (450 mg, 1.1 mmol) in dioxane (3 ml) was added conc. HCl (3 ml). The solution was stirred at 75° C. overnight. The mixture was concentrated in vacuo to give a yellow solid, which was purified by prep-HPLC to afford the pure trans isomer, the desired product in Example 3 (100 mg, 24%).
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[CH2:19][O:20][CH3:21])#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([CH2:3][CH:4]([N:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH:7]1[CH2:19][O:20][CH3:21])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCN1CC=CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)OC(C)(C)C)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 4-[3-cyanoprop-2-en-1-yl]-3-(methoxymethyl)piperazine-1-carboxylate (54 mg, 0.18 mmol; as a mixture of E- and Z-olefin isomers from Step 2) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (58 mg, 0.18 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.28 mL, 3.6 mmol) was treated with potassium carbonate (0.081 g, 0.58 mmol) and stirred for 5 h. The mixture was filtered and the filtrate was diluted with EtOAc, which was then washed with water (3 times), brine (once), dried over sodium sulfate, decanted and concentrated. Flash chromatography, using a 12 g silica gel cartridge and eluting with a gradient of 0-100% EtOAc in hexanes afforded an impure mixture of diastereomers which was used without further purification in the next step (91 mg, 57%). LCMS (M+H)+: 611.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[N:11]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (50 mg) in dichloromethane (1 ml) was added trifluoroacetic acid (250 μl). The resulting solution was stirred at room temperature for 2 hrs. Reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile and purified using the prep-HPLC to give the title compound trifluoroacetic acid salt as a white solid (6 mg).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].N1CCCCC1>C(O)(=O)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCc2ccccc21
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccc([N+](=O)[O-])cc2)Cc2ccccc21
Temperature: 95 °C

Procedure:
A mixture of indan-1-one (20.0 g), 4-nitrobenzaldehyde (27.0 g), glacial acetic acid (3.0 g) and piperidine (3.06 g) was heated at 95° C. under nitrogen for 3.5 h. The mixture was cooled to 20° C. and filtered to give a solid which was recrystallized from industrial methylated spirit to give 2-(4-nitrobenzylidene)indan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([N:8]1[CH:7]([CH3:20])[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9]1)=[O:27])[CH3:24]
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 69.4 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are boiled with 0.75 ml (9.5 mmoles) of ethyl isocyanate in 25 ml of anhydrous toluene for 24 hours. The mixture is evaporated, the residue is recrystallized from 5 ml of ethanol. Thus, 0.51 g (69%) of the title compound are obtained. M.p.: 170°-172° C.