Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].Br[C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][C:38]=1[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][C:38]=2[CH3:46])=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1nc2ccccn2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#C[Si](C(C)C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-bromo-2-methylimidazo[1,2-a]pyridine (842 mg, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 2 h at 60° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 0.6 g (34%). HPLC-MS: M+H=590; tR=2.05 min (*Method—3).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:27])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[NH:14][C:13]1=[O:23])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:23])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:27])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(c1)C(=Cc1[nH]cc(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (240 mg) suspended in ethylene glycol (2 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (1 pellet) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 30.5 mg (14%) of 3-[2-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [C:1]([C:8]1[CH:20]=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=3[CH2:18]2)=[CH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)Cl.[C:31](#[N:34])[CH:32]=[CH2:33]>CO>[C:31]([CH2:32][CH2:33][C:18]1([CH2:33][CH2:32][C:31]#[N:34])[C:17]2[CH:16]=[C:15]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=2[C:11]2[C:19]1=[CH:20][C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)#[N:34]
Reactant: CCCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCC)ccc1-2
Reactant: C=CC#N
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc2c(c1)C(CCC#N)(CCC#N)c1cc(C(=O)CCCCC)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A 3-neck 250-mL round bottom flask was equipped with a condenser, a nitrogen inlet, an addition funnel, and a magnetic stir bar. The flask was then charged with 14.50 g of 1-(7-hexanoyl-9H-fluoren-2-yl)-hexan-1-one and 80 mL of methylene chloride. TRITON B (0.80 g, 40% methanol solution) was then added, followed by the drop wise addition of acrylonitrile (4.67 g) at a rate that kept the reaction temperature below 35° C. The reaction was then stirred at ambient temperature for three hours. The solvent was then removed under reduced pressure and the resulting solid was crystallized from ethanol to give 12.60 g of the title compound. 1H NMR (CDCl3, 300 MHz) δ 8.11-8.03 (m, 4H), 7.89 (m, 2H), 3.04 (m, 4H), 2.55 (m, 4H), 1.81 (m, 4H), 1.56 (m, 4H), 1.44-1.38 (m, 8H), 0.94 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[NH:10][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:9])(=[O:14])[NH2:15]
Reactant: O=C(O)c1ccnnc1
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[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: NC(=O)c1ccccc1NC(=O)c1ccnnc1
Yield: 40 %

Procedure:
A mixture of pyridazine-4-carboxylic acid (500 mg, 4.0 mmol, 1.0 eq.), 2-aminobenzamide (603 mg, 4.4 mmol, 1.1 eq.) and HBTU (3.0 g, 8.0 mmol, 2.0 eq.) was suspended in 15 mL of DMF. DIPEA (2.0 mL, 1.56 g, 12.0 mmol, 3.0 eq.) was added dropwise at room temperature and was stirred over night. After quenching with water, the resulting precipitate was collected and washed with a small amount of DCM. A white solid (388 mg) was obtained, LCMS m/z=243.1 (M+1) (Method B) (retention time=0.99 min) was used in the next step without further purification.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:35]([O:43][CH2:44][CH:45]2[CH2:46][CH2:47]2)[CH:34]=1
Reactant: Nc1cc(OCC2CC2)c(C(=O)O)cc1Cl
Reactant: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OCC3CC3)C2)c2ccccc21

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide (1.00 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-cyclopropylmethyloxybenzoic acid (0.56 g) to give N-(4-(3-(4-amino-5-chloro-2-cyclopropylmethyloxybenzoylaminomethyl)-pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [N:1]([CH2:4][C:5](N)=O)=[N+:2]=[N-:3].ClCC[CH2:11][S:12]([NH2:15])(=[O:14])=[O:13]>>[N:1]([CH2:4][CH2:5][CH2:11][S:12]([NH2:15])(=[O:14])=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(N)=O
Reactant: NS(=O)(=O)CCCCl
Product: [N-]=[N+]=NCCCS(N)(=O)=O

Procedure:
The reaction was carried out similarly as described in the preparation of compound 411, using compound 3-chloro-propane-1-sulfonic acid amide (19.0 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 35:65 to 65:35 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])C1C=CC=CC=1.[C:18](O)(=O)[CH:19]([CH3:21])[CH3:20].Cl>>[OH:8][C:9]1[C:10]2[N:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:12]([CH3:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)O
Reactant: CNc1cccc(OCc2ccccc2)c1N
Agent: Cl
Product: CC(C)c1nc2c(O)cccc2n1C
Yield: 6.6 %

Procedure:
A mixture of 3-benzyloxy-2-amino-N-methylaniline (600 mg), isobutyric acid (243 mg) and 4N hydrochloric acid (3.5 ml) was refluxed for 3 hours, and the solvent was removed in vacuo. Chloroform and saturated sodium bicarbonate solution were added to the residue. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1, v/v) to give 4-hydroxy-2-isopropyl-1-methyl-1H-benzimidazole (33 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCCC[C@@H]5O)cnc4c4ccncc34)cn2)cn1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.070 g, 0.17 mmol) in 2 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.33 mL, 1 N aqueous, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.052 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (7.0 mg, 0.014 mmol) were added. After 5 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 466.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.64 (s, 1H), 9.03 (d, J=6.0 Hz, 1H), 8.80 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.35 (s, 1H), 8.19 (s, 2H), 8.13 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 4.18 (br s, 1H), 3.99 (s, 2H), 3.31 (s, 3H), 2.20 (br s, 1H), 2.00 (br s, 2H), 1.87 (br s, 2H), 1.52-1.39 (m, 4H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36].O>O1CCCC1>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][C@@H:27]1[CH2:26][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:8]=2)[N:12]([Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:25])[CH3:24])[CH:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C[C@H]2CCCN2C)c2cc(Br)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)c(C[C@H]1CCCN1C)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
n-ButylLithium (7.80 ml of a 2.5M solution in hexanes, 19.49 ml) was added dropwise to a solution of 5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1-triisopropylsilylindole (6.28 g, 13.97 mmol) (Preparation 58) in tetrahydrofuran (430 ml) at -78° C. The reaction was then stirred at -70° C. for 1/2 hour whereupon tri-n-butylstannylchloride (3.97 ml, 4.64 mmol) was added and the reaction stirred at -70° C. for 20 minutes. The reaction was then warmed to room temperature and 14.4 ml of water was added and the resulting solution partitioned (971/2:21/2) to afford, after combination and evaporation of the appropriate fractions, the title compound as an oil. Found: C,70.29; H,8.72; N,8.17. C30H43N3O2Si.1/8CH2Cl2 requires: C,70.07; H,8.44; N,8.14%.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:25])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[OH:24])[CH2:14]3)[C:10](=[O:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:40]CCCl)[C:34]1C=CC=CC=1>>[C:27]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:25])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:34][CH2:33][OH:40])[CH2:14]3)[C:10](=[O:26])[CH2:9][CH2:8]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCCOCc1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3OCCO)CC12

Procedure:
Following the procedure of Example 102 and using (3aRS,7aRS)-7,7-diphenyl-2-(2-hydroxyphenylacetyl)-4-perhydroisoindolone and 1-benzyloxy-2-chloroethane as starting materials, (3aRS,7aRS)-7,7-diphenyl-2-{2-[2-(2-hydroxyethoxy)phenyl]acetyl}-4-perhydroisoindolone (0.5 g) is obtained in the form of white crystals melting at 150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][CH:6]=[CH:5]2>C(O)C.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1Br
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
A mixture of 5-bromo-6-nitro-1H-indole (7.5 g, 31.1 mmol) and Raney Ni (1 g) in ethanol was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-1H-indol-6-ylamine (B-27) (2 g, 30%). 1H NMR (DMSO-d6) δ 10.6 (s, 1H), 7.49 (s, 1H), 6.79-7.02 (m, 1H), 6.79 (s, 1H), 6.14-6.16 (m, 1H), 4.81 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27])=[O:10]
Reactant: O=C(Cl)C1CC1
Reactant: O=C(Nc1cccc(I)c1)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccco1)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
3.19 g of furan-2-carboxylic acid (3-iodo-phenyl)-amide (Example 13bf)) are dissolved in 25 ml of methylene chloride with 2.78 ml of triethylamine and 100 mg of 4-dimethylaminopyridine. 1.60 g of cyclopropanecarbonyl chloride are added thereto and the mixture is stirred at room temperature for 5 hrs. The mixture is concentrated, poured into water and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 1.56 g of cyclopropanecarboxylic acid (furan-2-carbonyl)-(3-iodo-phenyl)-amide as a colourless solid. Yield: 58%. Mass spectrum: peaks inter alia at m/e: 381 (20%), 353 (28%), 313 (86%), 95 (75%), 69 (100%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=O)[C@H:6]([CH2:8][CH3:9])[CH3:7])(=[O:3])[CH3:2].C([O:20][C:21]1[CH:52]=[CH:51][C:24]([CH2:25][C@@H:26]([C:28]([NH:30][C@H:31]([P:47](=[O:50])([OH:49])[OH:48])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39]CC3C=CC=CC=3)=[CH:35][CH:34]=2)=[O:29])[NH2:27])=[CH:23][CH:22]=1)C1C=CC=CC=1>>[C:1]([NH:4][C@H:5]([C:10]([NH:27][C@H:26]([C:28]([NH:30][C@H:31]([P:47](=[O:48])([OH:50])[OH:49])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)=[O:29])[CH2:25][C:24]1[CH:23]=[CH:22][C:21]([OH:20])=[CH:52][CH:51]=1)=[O:12])[C@H:6]([CH2:8][CH3:9])[CH3:7])(=[O:3])[CH3:2]
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)P(=O)(O)O
Reactant: CC[C@H](C)[C@H](NC(C)=O)C(=O)O
Product: CC[C@H](C)[C@H](NC(C)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccc(O)cc1)P(=O)(O)O

Procedure:
Diethyl ester of N-(N-acetyl-L-isoleucyl-L-tyrosyl)-(R)-(-)-1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid was synthesized from N-acetyl-L-isoleucine and the compound 46a in the same condensation procedure as in Example 1 and then through the same reaction and treatment as in Example 8.
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[C:15]([O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: C=C1CC(C)(O)CCC2=C(C)CCC12
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CC(C)(OC(C)=O)CCC2=C(C)CCC12
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 6-hydroxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.1 ml of acetyl chloride. The mixture was left to stand overnight at room temperature, then poured on to ice and worked up in a conventional manner. The crude product (3.1 g) which was obtained in the form of a brown oil, was chromatographed on 50 times the amount of silica gel. By elution with hexane/ether (19.1) there was obtained pure 6-acetoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.01 ca 70°; IR(film): νmax = 3090, 1735, 1640, 1445, 1368, 1270/50/30, 1095, 1065, 1020, 905/900 cm-1. The compound has a flowery odour with a woody undertone.
Reaction SMILES: [CH3:1][CH:2]1[C@H:19]([C:20]([CH3:22])=[O:21])[C@:18]2([CH3:23])[C@H:4]([C@H:5]3[C@H:15]([CH2:16][CH2:17]2)[C@:14]2([CH3:24])[C:8](=[CH:9][C:10]([CH2:12][CH2:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:3][C@@H:4]2[C@:18]([CH3:23])([CH2:17][CH2:16][C@H:15]3[C@H:5]2[CH2:6][CH2:7][C:8]2[C@:14]3([CH3:24])[CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C@H:19]1[C:20](=[O:21])[CH3:22]
Reactant: CC(=O)[C@H]1C(C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A mixture of 16α-methylprogesterone (792 mg), DDQ (575 mg) and benzene are heated at reflux for 28 hr, after 20 hr additional DDQ (70 mg) is added. After refluxing, the mixture is cooled to 20°-25°, filtered followed by basic workup (ether-potassium carbonate-magnesium sulfate) to give 16α-methylpregna-1,4-diene-3,20-dione.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]1([CH3:14])[O:7][CH:6]1[CH2:8][CH2:9][C:10]([CH:12]=[CH2:13])=[CH2:11].[NH4+].[Cl-]>O1CCCC1.C(OC(C)C)(C)C>[CH3:4][C:5]([OH:7])([CH:6]([CH3:1])[CH2:8][CH2:9][C:10](=[CH2:11])[CH:12]=[CH2:13])[CH3:14]
Reactant: C[Mg]Cl
Reactant: C=CC(=C)CCC1OC1(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C=CC(=C)CCC(C)C(C)(C)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.6 %

Procedure:
1230 ml of a solution of CH3MgCl 3M in tetrahydrofurane (Fluka) was added to 26.5 g of CuBr (Fluka) in 11 of diisopropylether with stirring at 0° (bath temperature). After one night, the reaction mixture was cooled to −20° and 467 g of epoxymyrcene [2-(3,4-epoxy-4-methylpentyl)-1,3-butadiene] in 4 l of isopropylether were added dropwise. After the addition, the reaction mixture was warmed to room temperature. After 23 h the reaction was completed. After hydrolysis with a 15% NH4Cl-solution and washing with brine, the product was distilled to obtain 96.6% pure 2,3-dimethyl-6-methylene-7-octen-2-ol with a yield of 453.7 g (88%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(N(CC)CC)C>[CH:1]([NH:4][CH2:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)c1cccc(CBr)c1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(CNC(C)C)c1
Yield: 69.9 %

Procedure:
The procedure described in Referential Example 4 was repeated, except that isopropylamine (instead of triethylamine) (11.82 g; 200 mmol) and 3′-bromomethylacetophenone (4.26 g; 20 mmol) were used, to thereby yield 2.67 g of the target compound (yield: 69.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:39]=[C:40](F)[CH:41]=1)[C:25]([C:27]1[CH:37]=[C:36]([CH3:38])[C:30]2[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)=[O:26]>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:24]3[CH:39]=[C:40]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:41]=[C:22]([F:21])[CH:23]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(F)cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
440 mg (1.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 121 mg (0.40 mmol) 6-(3,5-difluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined and heated to 300° C. for approx. 10 min using the hot gun. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3=[CH:23][C:24]4[C:25](=O)[N:26]([CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[C:27](=[O:31])[C:28]=4[C:29]([CH3:30])=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:40][C:22]3=[CH:23][C:24]4[CH2:25][N:26]([CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[C:27](=[O:31])[C:28]=4[C:29]([CH3:30])=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)CN(C1CCN(C)CC1)C3=O
Yield: 15.1 %

Procedure:
A mixture of 2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.81 g, 1.46 mmol), zinc dust (0.95 g, 14.55 mmol), and 25 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.12 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.98 (s, 1H, NH), 11.32 (d, J=8.0 Hz, 1H, NH), 11.16 (d, J=4.5 Hz, 1H, NH), 7.80 (s, 1H, ArH), 7.29-7.26 (m, 1H, ArH), 7.15-7.12 (2H, ArH), 6.91-6.85 (m, 1H, ArH), 6.14 (d, J=7.5 Hz, 1H, ArH), 4.43 (s, 2H, CH2), 4.21-4.15 (m, 1H, CH), 4.04-3.99 (m, 1H, CH), 2.97 (d, J=6.5 Hz, 2H, CH2), 2.89-2.87 (m, 2H, CH2), 2.54 (s, 2H, CH2), 2.28 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.04-1.99 (m, 2H, CH2), 1.89 (s, 3H, CH3), 1.89-1.82 (m, 2H, CH2), 1.70-1.67 (m, 21-1, CH2), 1.34 (d, J=6.0 Hz, 3H, CH3); Mass (ESI, positive) m/z 543.2 [M+H]+; 565.2 [M+Na]+.