Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=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>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C(c1ccccc1)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
To a degassed solution of bromide 54 (0.33 g, 1.081 mmol), 4-methoxyphenylboronic acid (0.181 g, 1.190 mmol), POT (0.023 g, 0.076 mmol) and potassium carbonate (0.747 g, 5.41 mmol) in DME (15 mL) and water (7.5 mL) was added Pd(PPh3)4 (0.087 g, 0.076 mmol). The reaction mixture was stirred at 80° C. for 16 h and diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated to afford compound 55 (0.11 g, 31% yield) as a white solid after purification by ISCO (2 to 40% EtOAc/hexane).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12]O)=[CH:7][C:6]=1[CH3:14])(=[O:3])[CH3:2].[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][Br:15])=[CH:7][C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(CO)cc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)cc(CBr)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
To a solution of commercially available 4-(hydroxymethyl)-2,6-dimethylphenyl acetate (1 g, 5.15 mmol) and perbromomethane (2.39 g, 7.21 mmol) in tetrahydrofuran (25 mL) was added triphenylphosphine (1.620 g, 6.18 mmol). The mixture was stirred at room temperature for 6 hours then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane:ethyl acetate 4:1) to provide the title compound (1.05 g, 80% yield). MS (DCI/NH3) m/z 274 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1Cl
Temperature: 120 °C
Yield: 47.8 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (50.0 mg, 0.159 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (45 mg, 0.19 mmol), 10-camphorsulfonic acid (5.0 mg, 0.022 mmol) and isopropyl alcohol (2 mL) and heated at 120° C. for 30 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and extracted into EtOAc. The organic layer was washed with NaHCO3 and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue purified by chromatography (silica gel, 5% NH4OH in MeOH gradient with DCM). The appropriate fractions were combined and evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (39.0 mg, 48%) as a white powder that had the following properties: m.p.=146-147° C., bubbled, remelt at 184-187° C.; LC/MS (ESI+): 513 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.90 (s, 1H), 8.10 (s, 1H), 7.4-7.2 (m, 5H), 7.10 (d, J=8.5, 1H), 7.0 (s, 1H), 6.2, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].CN.C[CH2:37][N:38](CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:37][NH:38][C:21]([C:5]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:14][CH2:15]2)=[O:9])[N:6]=1)=[O:22]
Reactant: CCN(CC)CC
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with methylamine (solution in EtOH), Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 475.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Zn+]>C1COCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 60 °C
Yield: 64 %

Procedure:
Next, a pure solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (18 g, 54 mmol) in THF (˜200 mL) was treated with 2-pyridylzinc bromide 0.5 molar solution in THF (from Aldrich, brown color) (124 mL, 62.5 mmol, 1.15 eq.) followed by Pd(PPh3)4 (from Strem Chemicals) (625 mg). The reaction mixture was heated at 60° C. for 90 minutes. The THF was removed by rotary evaporator. Ethyl acetate (300 mL) and 1 N NaOH (200 mL) were added to the residue, and the zinc salts were removed by filtration. The organic layer was separated and washed with brine (300 mL), dried (MgSO4), and concentrated on the rotary evaporator to give brown oil. Purification by flash chromatography using Hexane:Ethyl acetate 6:4 as eluent gave 9.0 g (64% yield) of 3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 2.56 (m, 2H), 3.54 (t, 2H), 4.04 (m, 2H), 6.08 (m, 1H), 7.25 (dd, 1H), 7.56 (d, J=9 Hz, 1H), 7.77 (m, 1H), 8.54 (m, 1H); MS (DCI—NH3) m/z 259 (M+H)+, 277 (M+H+18)+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Br)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed 4-nitrobenzoyl chloride (22.6 g, 0.122 mol), bromobenzene (100 g, 0.63 mol), and aluminum chloride (17.3 g, 0.13 mol). The mixture was heated for 3 h at 100° C., then cooled to room temperature and stirred for an additional 16 h. The mixture was poured into 1 L of acidic (HCl) ice water, and the organics were extracted using methylene chloride, dried over magnesium sulfate, and the solvents were removed under reduced pressure to yield a yellow powder. Recrystallization from acetone afforded 29.2 g (85% yield) of yellow crystals: m.p. 123°-124° C., (Lit. 122° C.). ##STR5##
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CCN(CC)CC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])#[N:9]
Reactant: CCCC(=O)Cl
Reactant: Cc1nsc(N)c1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1snc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (5.31 g, 38.2 mmol) in DCM (200 mL) at 0° C., NEt3 (5 g, 50 mmol) was added followed by the dropwise addition of a solution of the butyryl chloride (4.88 g, 45.8 mmol) in DCM (50 mL). After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was washed with water (100 mL), 1N HCl (100 mL), brine (200 mL) and dried over Na2SO4. Concentration of the DCM layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate the pure N-(4-cyano-3-methyl-isothiazol-5-yl)-butyramide (7.57 g, 95%) as an orange solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([OH:33])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:54](Br)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([O:33][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:12][O:13][C:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
A 13.8 g portion of 1-(2-hexyl-5-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 40 ml of dimethylformamide was added dropwise to a suspension of 14.5 g of prewashed 50% sodium hydride in 40 ml of dimethylformamide and the mixture was stirred 15 minutes. A 4.45 g portion of benzyl bromide was added and the mixture was stirred an additional 3 hours. This mixture was quenched slowly with water and then extracted several times with ether. The ether extracts were combined, washed with water, brine, dried and evaporated, giving 15 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([C@@H:13]1[NH:17][C:16](=[O:18])[C:15]([F:20])([F:19])[C@@H:14]1[OH:21])[CH3:12].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:17]2[C@@H:13]([CH2:11][CH3:12])[C@@H:14]([OH:21])[C:15]([F:20])([F:19])[C:16]2=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (2.28 g), (4R,5S)-5-ethyl-3,3-difluoro-4-hydroxypyrrolidin-2-one (2.00 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (954 mg), tris(dibenzylideneacetone)dipalladium(0) (554 mg) and cesium carbonate (4.84 g), and in the same manner as in Example 62, the title compound was obtained as pale-yellow crystals (yield: 153 mg, 10%).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]>O1CCOCC1>[CH2:8]([O:7][C:5]([C:4]1[N:11]([CH2:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=[N:2][N:1]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOC(=O)C#N
Solvent: C1COCCO1
Product: CCOC(=O)Cn1nnnc1C(=O)OCC

Procedure:
A solution of ethyl azidoacetate (6.45 grams, 50 millimoles, 98.5 percent pure) and ethyl cyanoformate (10.0 grams, 100 millimoles) in 30 milliliters of dioxane was heated to reflux for 70 hours to insure complete reaction. The resulting reaction mixture was concentrated under vacuum to give 10.0 g. (88%) of the product as an oil. NMr indicated that the oil product was 88 percent pure; therefore, the actual yield from the reaction was 77 percent.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][C:15](ON1C(=O)CCC1=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([O:14][C:15]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCBr
Agent: Br
Solvent: ClCCl
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
TEA (6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3×), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].C(OC)(OC)OC.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1ccc2occc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: COC(OC)OC
Product: c1cc2cc(C3OCCO3)ccc2o1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of benzofuran-5-carbaldehyde (150 mg, 1.03 mmol), ethylene glycol (230 ul, 4 eq), trimethyl orthoformate (123 ul, 1.1 eq) and tetrabutylammonium tribromide (49 mg, 0.1 eq) was stirred at room temperature for one night. Some starting material could be detected by TLC. However, the reaction mixture was poured into saturated NaHCO3 solution and the product was extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated to give a crude product, which was purified by flash chromatography using cyclohexane/ethyl acetate 20:0.75 as solvents. The title compounds was obtained in 36% yield (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.I[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([O:17][CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(O)cc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(OC(C)C)cc12
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To methyl [6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 23, Step 2, 130 mg, 0.4 mmol) in DMF (1.5 mL) at r.t. was added 2-iodopropane (300 μL, 3 mmol) and Cs2CO3 (300 mg, 0.92 mmol). The reaction mixture was stirred for 15 minutes, and was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (100 mg).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=3)=[O:22])=[C:18]([NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([N:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]3)=[O:33])[C:17]=2[CH:43]=1)C)=O)(C)(C)C.[ClH:44]>O1CCOCC1>[ClH:30].[ClH:44].[ClH:30].[CH3:42][N:40]([CH3:41])[C@H:37]1[CH2:38][CH2:39][C@H:34]([C:32]([NH:31][C:18]2[C:17]3[CH:43]=[C:13]([O:12][CH2:11][CH2:10][NH:8][CH3:6])[CH:14]=[CH:15][C:16]=3[O:20][C:19]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:33])[CH2:35][CH2:36]1
Reactant: CN(CCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-5-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (300 mg) obtained in Example 36 is dissolved in dioxane (5 ml), and thereto is added 4N hydrogen chloride in dioxane (10 ml), and the mixture stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration, and dried to give the title compound (301 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:31][NH2:32]>C1COCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([NH:31][NH2:32])=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(O)[C@H]1CC[C@H](Oc2ncccn2)CC1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ncccn2)CC1
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-(pyrimidin-2-yloxy)-cyclohexanecarboxylic acid (1:2) (0.258 g, 1.16 mmol) and triethylamine (0.162 ml, 1.16 mmol) in THF (6 ml) was added ethyl chloroformate (0.111 ml, 1.16 mmol) at 0° C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.116 g, 2.32 mmol) in methanol (10 ml). The reaction mixture was stirred for 2 h at room temperature and then partitioned between ethyl acetate (50 ml) and a mixture of a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine (50 ml). The layers were separated. The aqueous layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.177 g, 65%) as white solid, which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:41][OH:42])[CH2:3][N:4]([CH3:40])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53]>ClCCl>[CH3:40][N:4]([CH2:3][CH:2]1[CH2:41][O:42][C:52](=[O:53])[O:1]1)[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:37])([F:38])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC4COC(=O)O4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.50 g, 0.87 mmol) in dichloromethane (17 mL) at 0° C. was added N,N-diisopropylethyl amine (0.30 mL, 1.72 mmol) followed by 1,1′-carbonyldiimidazole (0.14 g, 0.87 mmol). The reaction was allowed to warm to room temperature while stirring overnight then concentrated in vacuo to give a white solid. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography using a solvent system of 80% ethyl acetate in hexane provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.48 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1.CC[O:45]CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1.[C:35]([O-:41])(=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([O-:45])=[O:40]
Reactant: CCOCC
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 80 °C

Procedure:
In a 500 mL round bottom flask curcumin (3.00 g), DMAP (168 mg) and triethyl amine (4 ml) were taken in 150 mL of THF. Glutaric anhydride (2.35 ml) in 15 mL of THF was added drop-wise under anhydrous conditions. The mixture was refluxed for 20 hours at 80° C. The solution was evaporated in a rotovop. The thick residue was taken in 150 mL of ethyl acetate, washed with 50 mL of 0.5 N HCl. The HCl wash was extracted with 50 mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and was concentrated under vacuum to get 4.80 g. This was co-evaporated with ether several times to get a solid, 2.5 g. NMR was consistent with the structure.