Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].N>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:11][CH:12]([CH3:27])[CH3:13])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Agent: N
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 150 mg, 61%). mp 116-117° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 3.3 (s, 3H), 4.2 (d, 2H), 7.54 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H), 7.91 (d, 2H), 8.07 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 435 (M+H)+, 452 (M+NH4)+. Anal. calc. for C21F2H20N2O4S: C, 58.06; H, 4.64; N, 6.45.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]2[CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[C:20](=[O:21])[C:3]=12.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[C:7](=[O:8])[C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:3]3[C:20](=[O:21])[N:19]([CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH2:18][C:4]3=[CH:5]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2cc3c(c(Cl)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3)cc1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc3c(c(N4CCOCC4)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3)cc1
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of 7-chloro-5-(4-methoxy-benzyl)-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (65 mg, 0.141 mmol, see Example c7)), morpholine (12.31 mg, 0.141 mmol), Xantphos (82 mg, 0.141 mmol), palladium diacetate (31.7 mg, 0.141 mmol) and Cs2CO3 (138 mg, 0.424 mmol) in dioxane (5 ml) was heated in a CEM microwave at about 120° C. for about 30 min. The solvent was removed and the crude material was purified via preparative thin-layer chromatography (MeOH/DCM=5:95) to give the title compound (30 mg, 0.056 mmol, 39.5% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][CH2:17]O>>[CH2:16]([O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14])[CH3:17]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CCO
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
5-Nitro-benzofuran-2-carboxylic acid (500 mg, 2.41 mmol) was esterified with EtOH using Method A to give the title compound.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>ClCCl.O.CS(C)=O>[C:33]([S:35][CH:17]1[CH2:18][CH2:19][N:14]([CH:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:15][CH2:16]1)(=[O:36])[CH3:34]
Reactant: CC([O-])=S
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)CC1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
8.0 g (28.9 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-hydroxypiperidine were dissolved in 50 ml of dichloromethane, followed by the addition of 2.92 g (28.9 mmol) of triethylamine. A 10 ml dichloromethane solution of 3.31 g (28.9 mmol) of methanesulfonyl chloride was added dropwise under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure. Ethyl acetate was added to the residue and the triethylamine hydrochloride thus precipitated was filtered off. The filtrate was concentrated under reduced pressure, whereby crude 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-methylsulfonyloxypiperidine was obtained. To the resulting crude product were added 50 ml of dimethyl sulfoxide (DMSO) and 19.8 g (170 mmol) of potassium thioacetate and the resulting mixture was stirred at 50° C. for 4 hours. Water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=19/1), whereby a reddish brown oil was obtained. The oil was then crystallized from hexane, whereby 3.6 g of 4-acetylthio-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)piperidine were obtained as pale brown crystals (yield: 37%).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O=S(Cl)Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH2:30]O)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:30][CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:32])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:11])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Yield: 80.9 %

Procedure:
A mixture of 5-chlorosulfonyl-2-methoxybenzoic acid (Intermediate 6, 3.0 g, 12.0 mmol) and SOCl2 (6 mL) was heated to reflux temperature for 2 h. Then excess SOCl2 was removed by distillation. The resulting residual oil was dissolved in 20 mL of CH2Cl2 and 2-(p-toluenesulfonyl)ethanol (available from Aldrich 2.0 g, 10 mmol) in 10 mL of CH2Cl2 was added at room temperature. The resulting mixture was heated to reflux temperature for 3 h. Thereafter volatile materials were removed under reduced pressure and the residual oil was purified by column chromatography (silica gel, hexane:CH2C2=1:1 to CH2Cl2) to give 3.5 g (81%) of 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (Intermediate 7) as clear thick oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].Cl>>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1scc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(C(=O)O)c1N
Temperature: 0 °C
Yield: 65.2 %

Procedure:
Methyl 3-amino-4-methylthiophene-2-carboxylate (4.67 g, 27.3 mmol) and NaOH (2N in H2O, 68 mL, 136 mmol) were stirred at 100° C. for 1 hour. The solution was cooled to 0° C. and acidified to pH=5 with addition of concentrated HCl solution to form a precipitant. The solution was filtered and the solid was dried under vacuum to give the title compound (2.8 g, 65%).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])[N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])[N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C(=O)O)c1cn2nc(NCCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
1.56 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 617 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 185° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration. The residue was dissolved in 4 ml of ethanol; 4 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 4 hours; 1 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by stirring at 50° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was powdered by the addition of ethyl acetate, collected by filtration and dried to yield 271 mg of the title compound.
Reaction SMILES: C1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:8]([O:12][CH2:13][CH:14]=C)[CH2:9][CH:10]=C)C=CC=CC=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:7]([C@H:8]1[CH2:9][CH:10]=[CH:14][CH2:13][O:12]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCO[C@H](CC=C)C(c1ccccc1)c1ccccc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: C1=CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 177.5 %

Procedure:
(2R)-1,1-Diphenyl-2-Allyloxy-Pent-4-en 26b (0.25 g, 0.90 mmol) was cyclized in the presence of Grubb's catalyst (0.037 g, 0.045 mmol) (Procedure C) to produce (2R)-2-Benzhydryl-3,6-dihydro-2H-pyran 27b 0.2 g (89%, [α]D=(+)80.8, c=1, MeOH). The 1HNMR and 13CNMR were identical with (2S)-2-benzhydryl-3,6-dihydro-2H-pyran 27a.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[NH4+:16].O.C(O)(=O)CCCCCCCCCCC>O>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH4+:16]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
A 7 wt.% ammonium laurate solution was prepared by mixing 0.7 weight part (0.476 mole) of lauric acid with 9.3 weight parts of demineralized water at 50° C. 0.304 Part of a 28 wt.% solution of ammonium hydroxide in water was added slowly with stirring to the water-lauric acid mixture. An ammonium laurate solution formed and was cooled to room temperature. The solution had a 9.8 pH and a 1.43 NH3 /lauric acid molar ratio.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]#[C:11][C:12]([OH:14])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:12](=[O:14])[C:11]#[C:10][CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[CH2:3][O:2][CH3:1])[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: COC[C@@H]1CCCN1CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: COC[C@@H]1CCCN1CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 1.46 g (7.40 mmol) of 4-((2S)-2-methoxymethylpyrrolidin-1-yl)but-2-ynoic acid in 85 mL of THF under N2 was added 0.897 g (8.88 mmol) of N-methylmorpholine and 0.811 g (5.92 mmol) of isobutyl chloroformate. After stirring in the cold for 30 min, a solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile in 8 mL of pyridine was added dropwise. The reaction was slowly warmed to 25° C. over 3 h. The reaction was poured into ice water, satd NaHCO3 was added and the product was extracted with ethyl acetate. After drying and solvent evaporation, the residue was chromatographed on silica gel (10% methanol in ethyl acetate). The yield was 0.560 g of 4-((2S)-2-methoxymethylpyrrolidinyl-1-yl)but-2-ynoic acid[4-(3-bromophenylamino)-3-cyanoquinolin-6-yl]amide as a brown foam: mass spectrum (electrospray, m/e): M+H 518.0, 520.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:37]([N:36]([CH3:40])[CH3:35])=[O:38])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C2=CCNCC2)cc2c(Cl)ncnc21
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 15 °C
Reaction time: 5 h

Procedure:
To a solution of Example 75B (4.25 g, 10.33 mmol) and diisopropylethylamine (5.41 ml, 31.0 mmol) in 120 mL dichloromethane was added dimethylcarbamic chloride (1.333 g, 12.40 mmol). The mixture was stirred at 15° C. for 5 hours. The reaction was concentrated in vacuo, and the crude material was purified via flash chromatography: Analogix Intelliflash™ 280, 80 g silica column, 1:1 hexane/ethyl acetate to give the title compound. LC-MS (ESI+) m/z 446.0 (M+H)+.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:12]=1[C:21]([O-:23])=O.[Si:24]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][NH2:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Si:24]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][NH:35][C:21]([C:12]1[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:4]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:3]=1[F:2])=[O:23])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Reactant: Cn1c(C(=O)[O-])c(Nc2ccc(I)cc2F)c2cnccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](CONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid sodium salt (0.20 g, 0.46 mmol), O—[(S)-2-(tert-butyldimethylsilanyloxy)-propyl]-hydroxylamine (95 mg, 0.46 mmol), HOBT (69 mg, 0.51 mmol), EDCI (97 mg, 0.51 mmol) and DIPEA (0.08 ml, 0.46 mmol) were suspended in a mixture of THF (3 ml) and DMF (1 ml). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (20 ml) and washed with aqueous saturated sodium bicarbonate solution (20 ml). The aqueous layer was isolated and extracted with ethyl acetate (2×10 ml) and the combined organic layers dried, washed with brine and dried over magnesium sulfate before concentrating in vacuo. The crude residue was purified by flash chromatography (SiO2, gradient 1-3% methanol in dichloromethane) to yield the title compound as an off-white solid (171 mg, 62%). LCMS (method B): RT=3.00 min, M+H+=599.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32]([CH2:33][N:34]1[CH2:35][CH2:36][N:37]([CH2:14][CH:12]([OH:13])[CH2:11][C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:15])[CH2:38][CH2:39]1)=[O:40]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: COc1ccc(NC(=O)CC2CO2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)CC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
To a solution of crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide (10) in ethanol (2.5 mL) was added triethylamine (0.5 mL), followed by N-(2,6-dimethylphenyl)-2-piperazinylacetamide, a compound of formula (4) (150 mg), and the mixture was heated to reflux for 18 hours. Solvent was removed from the reaction mixture under reduced pressure, and the residue purified by column chromatography on silica gel, eluting with 5% MeOH/dichloromethane, to give 4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(4-methoxyphenyl)butanamide, a compound of Formula I as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([N:30](C)[C:31](=O)OC(C)(C)C)=[N:28][CH:29]=3)=[CH:19][CH:18]=4)=[C:9]([O:39][CH3:40])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:29]=[N:28][C:27]([NH:30][CH3:31])=[CH:26][CH:25]=3)=[CH:19][CH:18]=4)=[C:9]([O:39][CH3:40])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:41]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3)ccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2ccc3cnc(Nc4ccc(-c5cnc(C)n5C)cc4OC)cc3c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (5-(3-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-amino)isoquinolin-6-yl)pyridin-2-yl)(methyl)carbamate (Example 12, 10 mg, 0.018 mmol) in DCM (4 mL) at 0° C. was added TFA (0.6 mL). The reaction was stirred at room temperature for 16 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a yellow oil (8 mg, 98%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][C:15](=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C@@H:10]1[C@H:22]1[O:26]C(C)(C)[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:29]([NH:24][C@@H:23]([CH2:32][C:33]1[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=1)[C@@H:22]([C@@H:10]1[NH:9][CH2:13][C@H:12]([O:14][C:15](=[O:21])[NH:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:11]1)[OH:26])(=[O:31])[CH3:30]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OC(=O)NC(C)(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OC(=O)NC(C)(C)C)CN1
Reaction time: 4 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (5 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-tert-butylcarbamoyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.34 g, 0.616 mmol). Stir 4 hours and evaporate to give the title compound as a foam (0.291 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH:35]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH:35]([CH3:37])[CH3:36])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CC(C)OCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCOC(C)C)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.52 g, 1.10 mmol) and 4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.60 g, 1.08 mmol) to give the title compound; Rf=0.28 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5](Br)=[C:6]([OH:8])[CH:7]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].NC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:6]([OH:8])=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc(O)c(Br)cc1Br
Reactant: C/C=C/C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2c(O)cccc2n1

Procedure:
To a stirred mixture of the 5-amino-2,4-dibromophenol prepared in example 3 (13 g, 49 mmol), acetic acid (65 mL) and HCl (65 mL) was added crotonaldehyde and the resultant mixture was heated at reflux for 1.5 h under argon. HBr (65 mL) and aniline (13 mL) were added and the mixture was refluxed for 5 h. After cooling, the reaction mixture was neutralized by adding of NaHCO3 (˜180 g) and then extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give a black solid (22 g). The crude product was purified by column chromatography (eluents: CH2Cl2-MeOH 98:2). Yield 5 g (49%) brown-white solid. Rf=0.43 (CH2Cl2-MeOH 9:1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]1([O-])[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[N:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:7]1[CH:8]=[N:9][C:10]2[C:15](=[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]3=[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]3=2)[N:6]=1
Reactant: [O-][n+]1ccnc2c3ccccc3c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1cnc2c3ccccc3c3ccccc3c2n1
Yield: 93 %

Procedure:
Next, 18 mL of phosphoryl chloride was dripped into 2.91 g of dibenzo[f,h]quinoxaline-1-oxide obtained in the above Step 1. This mixed solution was stirred while being heated under reflux for 1 hour. This mixed solution was poured into iced water, followed by addition of potassium carbonate so that the mixture was alkaline. This solution was filtered, and the obtained residue was washed with water and then methanol to give the object of the synthesis (as a pale yellow powder in a yield of 93%). The synthesis scheme of Step 2 is illustrated in the following (a″′-2-2).