Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:85]1[CH2:90][CH2:89][O:88][CH2:87][CH2:86]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.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].O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([NH2:16])=[CH:3][C:2]([N:85]3[CH2:90][CH2:89][O:88][CH2:87][CH2:86]3)=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2ncc(Br)cc2N)cc1
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2N)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine (424.5 mg, 1.52 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (58.8 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (0) (56.1 mg, 0.061 mmol), and morpholine (0.66 mL, 7.58 mmol) in dry THF (3.2 mL) was degassed by nitrogen. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0M in THF (8.4 mL, 8.40 mmol) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-100% DCM in EtOAc) to yield 2-(4-methoxyphenyl)-5-morpholinopyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, d, J=2.5 Hz), 7.57 (2H, m), 6.98 (2H, m), 6.53 (1H, d, J=2.5 Hz), 3.92 (9H, m), 3.22 (4H, m). Mass Spectrum (pos.) m/e: 286.1 (M+1).
Reaction SMILES: [CH:1]1([Si:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16](O)(C)C.C[Si](C)(C)Cl>[O-]CC.[Na+]>[CH:11]([O:10][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:13][CH2:14][CH3:15])[O:7][CH2:8][CH3:9])([CH3:16])[CH3:12]
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Reactant: CC(C)O
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)C)C1CCCC1
Yield: 46.1 %

Procedure:
In a 500 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 19.6 g (0.0841 mole) of cyclopentyl triethoxysilane, 98.0 g (1.63 mole) of isopropyl alcohol and 198.7 mg (2.92 m mole) of sodium ethoxide, which were then reacted with each other at room temperature for 2 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 9.56 g (0.0388 mole) of isopropoxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. Tile yield was 46%.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:21](=[O:22])[NH:20][C@H:4]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[CH3:3])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: c1ccccc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@@H](C)c3ccccc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester in DCM was added (S)-1-Isocyanato-ethyl)-benzene (5 equiv) and the reaction was stirred at rt for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 886.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:62][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:28][C:29]([O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)=[O:39])[C@H:15]([OH:40])[CH2:14][N:13]([S:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:19][CH:20]=2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-hydroxyethoxy)benzyl]propylcarbamate (0.11 g, 0.18 mmol), triethyl amine (0.055 mL, 40 mg, 0.39 mmol), and 4-dimethylaminopyridine (2 mg), in dichloromethane at 0° C. was added p-toluenesulfonyl chloride (38 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 4 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound as a solid foam (0.105 g). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.38 (3H, s), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, d), 4.3 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.7 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.22 (1H, s), 7.29 (1H, d), 7.4 (2H, d), 7.8 (2H, d); MS: 791 (MH+)
Reaction SMILES: CO.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH2:26][CH:27]=[CH2:28])[C:23]([OH:29])=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4].O=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[C:23]4[O:29][C:27]([CH3:28])=[CH:26][C:24]=4[CH:25]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OC)c1O
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)OC)c4oc(C)cc4c3)cs2)cc1OCC
Reaction time: 10 h
Yield: 23.1 %

Procedure:
In a mixed solvent consisting of 50 ml of methanol and 5 ml of water were suspended 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazole, 50 mg of palladium acetate [Pd(OAc)2 ] and 230 mg of copper acetate [Cu(OAc)2. H2O]. The suspension was stirred in an oxygen atmosphere at 50° C. for 6 hours. 50 mg of palladium acetate was further added. After 10 hours, 50 mg of palladium acetate was furthermore added. After 14 hours, when no solid starting materials in the reaction mixture were visible, the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane=1/1 by v/v) and recrystallized from methanol-dichloromethane to obtain 230 mg of 2-(3,4-diethoxyphenyl)-4-(2-methyl-7-methoxycarbonyl-5-benzofuryl)thiazole.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([OH:31])=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]([CH2:63][S:64](=[O:67])(=[O:66])[NH2:65])[C:59]([O:61][CH3:62])=[O:60]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([NH:57][CH:58]([CH2:63][S:64](=[O:67])(=[O:66])[NH2:65])[C:59]([O:61][CH3:62])=[O:60])=[O:31])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: COC(=O)C(N)CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(CS(N)(=O)=O)NC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
To a solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (50.0 mg, 0.119 mmol) in DMF (1 mL) was added DMAP (22.0 mg, 0.178 mmol) followed by HATU (68.0 mg, 0.178 mmol) and the reaction mixture stirred for 10 minutes at room temperature. Methyl 2-amino-3-sulfamoylpropanoate (10.8 mg, 0.0590 mmol) was added and the reaction mixture stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the resulting residue and the solution extracted with DCM (2×25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-102 as described in general methods) to obtain (methyl 2-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamido)-3-sulfamoylpropanoate (10.0 mg, 27.6%). LCMS Condition B-19: retention time 2.11 min, [M+1]=586.1. HPLC Condition B-30: retention time 11.20 min, Purity 98.0%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.65 (d, J=6.3 Hz, 2H), 3.71 (s, 3H), 4.84 (d, J=5.8 Hz, 2H), 4.93 (d, J=7.1 Hz, 1H), 6.72 (t, J=5.6 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 7.08 (br s, 2H), 7.21-7.29 (m, 1H), 7.31-7.42 (m, 5H), 7.44-7.52 (m, 2H), 7.53-7.57 (m, 2H), 7.93 (d, J=2.8 Hz, 1H), 8.95 (t, J=2.1 Hz, 1H), 9.09 (d, J=2.1 Hz, 1H), 9.44 (d, J=7.8 Hz, 1H), 9.50 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-])=O>[Pd].CO>[NH2:21][C:4]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(Oc2c(F)c(F)c(F)c(F)c2F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(Oc2c(F)c(F)c(F)c(F)c2F)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
A mixture of N-methyl-N-[2-nitro-5-(pentafluorophenoxy)phenyl]amine (2.10 g), palladium on carbon (10%, 0.23 g) and methanol (300 ml) was stirred under a hydrogen atmosphere at ambient temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=3/1 as the eluant to give N-[2-amino-5-(pentafluorophenoxy)phenyl]-N-methylamine (1.48 g), of which Rf was 0.26 in thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=4/1. A mixture of this product, glycolic acid (0.76 g), 4N hydrochloric acid (25 ml) and dioxane (25 ml) was heated at reflux for 16 hours. The reaction mixture was concentrated and water was added to the residue. The mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a silica gel column using ethyl acetate/methanol=20/1 as the eluant. The product was crystallized from n-hexane under irradiation of ultrasonic wave. The crystals were collected by filtration and washed with n-hexane to give the title compound (1.17 g).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([OH:13])CO)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I([O-])(=O)(=O)=O.[K+]>O>[C:1]([NH:8][CH2:9][CH:10]=[O:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Agent: [K+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 2.5 h

Procedure:
3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6×400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93%) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84° C. and 0.3 mmHg in two portions. The yield 79 g (77%) of a colorless oil.
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:14]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7].C[O-].[Na+].[Na].CC1C=CC(S(NCl)(=O)=O)=CC=1.[CH3:52][NH2:53].C(O)C>C1COCC1.CO.C(=O)(O)[O-].[Na+].O>[CH3:52][NH:53][S:6]([C:9]1[CH:14]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:7])=[O:8]
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccnc(S(=O)(=O)CCC(=O)OC)c1
Reactant: CN
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccnc(S(=O)(=O)NC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of 3-[4-(1-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-butyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (200 mg, 0.39 mmol) in anhydrous THF (10 mL) is added sodium methoxide in methanol (2.6 M solution freshly prepared by dissolving 140 mg of sodium in 2.4 mL of methanol, 0.15 mL, 0.39 mmol). After stirring at room temperature for 10 min, the reaction mixture is concentrated in vacuo. Anhydrous THF (10 mL) is added and the concentration process is repeated. The resultant residue is dried under high vacuum for 5 min, dissolved in THF (10 mL) and treated with chloramine T (180 mg, 0.77 mmol). The reaction mixture is stirred at room temperature for 15 min and then treated with methyl amine in ethanol (33% solution in ethanol, 0.48 mL, 3.9 mmol) in one portion. After 20 min the reaction mixture is diluted with saturated aqueous sodium bicarbonate (20 mL) and water (8 mL), and extracted with EtOAc (2×35 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(2-methylsulfamoyl-pyridin-4-yl)-butyl]-amide (160 mg, 90%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C#CC(=O)OCCOCCOC

Procedure:
12.3 ml (0.2 mol) of propiolic acid are heated at reflux for 20 hours together with 23.6 ml (0.2 mol) of diethylene glycol monomethyl ether, 1.5 g (8 mmol) of p-toluenesulphonic acid monohydrate and 80 ml of toluene, and the resulting reaction water was distilled off azeotropically and collected in a water separator. After completion of the water separation the reaction mixture was washed in succession with saturated sodium bicarbonate solution and with water. The toluene phase was dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 2-(2-methoxyethoxy)ethyl propiolate as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.[CH3:12]C12CCCCC1C(=O)OC2=O>>[CH2:12]1[CH:10]2[CH:2]3[C:1](=[O:11])[O:6][C:4](=[O:5])[CH:3]3[CH:7]1[CH:8]=[CH:9]2
Reactant: CC12CCCCC1C(=O)OC2=O
Reactant: O=C1OC(=O)C2CCC=CC12
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
tetrahydrophthalic anhydride (referred to as THPA); and methylhexahydrophthalic anhydride (referred to as Me-HHPA).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([O:29][C:30](=[O:61])[NH:31][CH:32]([C:35](=[O:60])[NH:36][CH:37]([C:46](=[O:59])[N:47]([CH2:51][CH:52]([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])[CH:48]([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[CH2:33][NH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:61])[NH:31][CH:32]([C:35](=[O:60])[NH:36][CH:37]([C:46](=[O:59])[N:47]([CH2:51][CH:52]([O:53][CH2:54][CH3:55])[O:56][CH2:57][CH3:58])[CH:48]([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[CH2:33][NH:34][S:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])(=[O:20])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CN)NC(=O)OCc1ccccc1)C(C)C)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.94 ml (11.09 mmol) of DIEA and 1.5 g (6.1 mmol) of 2,4-dichlorophenylsulfonyl chloride are added to a solution of 3.2 g (5.54 mmol) of benzyl(2-amino-1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 75 ml of DCM. The solution is stirred at room temperature overnight. The solution is then concentrated in vacuo, and the residue is purified by column chromatography on 100 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM). 2.78 g of the desired product are obtained as a colorless foam. MW=784.19 (calculated, monoisotopic); measured value (M+Na)+=807.24
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[CH2:8]([O:15][CH:16]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([O:19]CC1C=CC=CC=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:8]([O:15][CH:16]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([OH:19])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)C(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Yield: 96.9 %

Procedure:
Water (20 ml) and potassium carbonate (10.64 g) were added to a solution of benzyl dibenzyloxyacetate (11.15 g, prepared as described in Step 1 above) in tetrahydrofuran (80 ml) and the mixture heated under reflux for twenty-four hours. It was allowed to cool, poured into water, extracted with ether, acidified with concentrated hydrochloric acid and again extracted with ether. The extract from acidic solution was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (8.12 g), used crude in Step 3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Fc1ccc(N2CC3CN(Cc4ccccc4)CC3C2)cc1
Yield: 71 %

Procedure:
2-Benzyloctahydropyrrolo[3,4-c]pyrrole (50.0 mg, 0.247 mmol), 1-bromo-4-fluorobenzene (33.0 μL, 0.303 mmol), and sodium tert-butoxide (144 mg, 1.50 mmol) were used to obtain the title compound (52.0 mg, yield 70%) by synthesis in a similar manner to Reference Synthesis Example 23.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[CH2:3]1.I[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.CN(C)C=O>[Cu]I.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(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:4](=[O:21])[CH2:3]1
Reactant: C#Cc1ccc2c(c1)N(c1ccc(C)cc1)C(=O)CC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)C(=O)CC3(C)C)cc1
Temperature: 50 °C

Procedure:
To a mixture of 0.13 g (0.45 mmol) of 4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-7-ethynyl-2(1H)-quinolinone (Compound 20) and 0.29 g (1.0 mmol) of ethyl 4-iodobenzoate were added 2.9 g (4.0 mL, 29 mmol) of triethylamine, 2.0 mL of dimethylformamide, 0.019 g (0.10 mmol) of copper(I)iodide, and 0.067 g (0.10 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 50° C. for 16 hours. Thereafter methylene chloride was added and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (15% ethyl acetate in hexanes) to give the title compound as an orange solid. PNMR (300 MHz, CDCl3) d 1.41 (3 H, t, J=7.1 Hz), 1.43 (6 H, s), 1.86 (2 H, t, J=6.0 Hz), 2.44 (3 H, s), 2.48 (2 H, s), 4.37 (2 H, q, J=7.1 Hz), 6.59 (1 H, d, J=1.5 Hz), 7.12 (2 H, d, J=8.3 Hz), 7.20-7.38 (4 H, m), 7.50 (2 H, d, J=8.1 Hz), 7.98 (2 H, d, J=8.1 Hz).