Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([CH3:36])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([CH3:36])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A mixture of {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazol-4-yl}methanol (0.27 g), activated manganese dioxide (0.90 g) and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carbaldehyde as colorless crystals (0.22 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 121-122° C.
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][O:30]CC1C=CC=CC=1)=[O:25])=[O:15])=[O:11])C1C=CC=CC=1>CN(C=O)C.[Pd]>[OH:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][OH:30])=[O:25])=[O:15])=[O:11]
Reactant: O=C(COC(=O)COCc1ccccc1)NCCCCCCNC(=O)COC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(COC(=O)CO)NCCCCCCNC(=O)COC(=O)CO
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Benzyloxy-acetic acid {6-[2-(2-benzyloxy-acetoxy)-acetyl amino]-hexylcarbamoyl}-methyl ester (250 g) was dissolved in DMF (600 ml) in a pressure vessel (Autoclave), 50% wet palladium on carbon (10%, 75 g) was added and the mixture was stirred under hydrogen atmosphere (8 Kg) for 72 hours at 70° C. The catalyst was removed by filtration and 80% of the DMF was distilled off. The crude product was precipitated by adding to Methanol and filtered and dried to get pure (Hydroxy-acetic acid {6-[2-(2-hydroxy -acetoxy)-acetylamino]-hexylcarbamoyl}-methyl ester) (90 g) as a white powder with a melting point of 156-158° C. The pure product was characterized by IHNMR (CDC13+DMSO-d6) δ 1.22 (m, 2H, CH2), 1.38 (m, 2H, CH2), 3.06 (m, 2H, CH2), 4.15 (d, 2H, CH2), 4.48 (s, 2H, CH2), 5.42 (t, 1H, OH), 7.98 (bt, 1H, NH).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2>[Pd].CO.C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)C=Cc1csc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1csc2ccccc12

Procedure:
A suspension of 3-benzo[b]thiophen-3-yl-acrylic acid: (5.6 g, 0.027 mol) and 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (50 mL) was hydrogenated in a Parr apparatus at 50 psi overnight. The mixture was filtered and concentrated to give the crude product without further purification (ca. 100% conversion). Mass spec.: 205(MH)−.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14](=[O:46])[CH2:15][N:16]([S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N(S(=O)(=O)C(F)(F)F)CS(=O)C12
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (1.172 g.) in methylene chloride (10 ml.) was added dropwise a solution of m-chloroperbenzoic acid (430 mg.) in methylene chloride (6 ml.) at 0° C. with stirring over a period of 20 minutes, and the mixture was stirred for an additional 15 minutes. The mixture was diluted with methylene chloride and washed with a chilled dilute aqueous solution of sodium bicarbonate and a mixture of a dilute aqueous solution of sodium chloride and an aqueous solution of sodium bicarbonate. Drying over magnesium sulfate and removal of the solvent left an amorphous solid (1.2 g.), which was chromatographed on silica gel (17 g.) with methylene chloride and then a mixed solvent of methylene chloride and ethyl acetate as an eluent to give an amorphous solid (1.10 g.) of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate-5-oxide.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-methoxyphenyl-isocyanate.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1.[OH-].[K+].Cl>C(O)C>[CH3:1][CH:2]([CH3:22])[CH:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(OC(c2ccccc2)C(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(Oc1ccc(C(=O)O)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 13-5 (8.89 g, 29.8 mmol) was added 2N potassium hydroxide (100 ml) and ethanol (50 ml). The mixture was stirred at 100° C. overnight. The ethanol was removed in vacuo and the aqueous solution was cooled in ice and acidified with 6N HCl (35 ml, 0.21 mol). The acid was extracted into ethyl acetate (50 ml) and the extract was washed with water, dried, filtered and concentrated in vacuo to obtain the oil 13-6, which solidified. The white solid melted at 125°-129° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:15])=[C:9]([C:13]#[N:14])[NH:10][C:11]=1[CH3:12])=O.[N+]([O-])(O)=O.[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>COCCO>[CH3:15][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:33]=[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[N:32]=2)=[C:11]([CH3:12])[NH:10][C:9]=1[C:13]#[N:14]
Reactant: Cc1[nH]c(C#N)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1[nH]c(C#N)c(C)c1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 120 °C

Procedure:
To a mixture of 4-(3-dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.0 mmol, 0.22 g) and 3-nitrophenyl guanidine nitrate (1.5 mmol, 0.36 g) in 2-methoxyethanol (5 mL) was added K2CO3 (138 mg, 1.0 mmol). The reaction mixture was heated at 120° C. under N2 for 18 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (1:2 EtOAc/heptane) to afford the title compound as a light-yellow solid. M.p. 258–259° C. MS: [M+H]+=336.1 (C17H14N6O2 requires 334.3). 1H-NMR (CD3OD) δ: 2.39 (s, 3H, CH3), 2.49 (s, 3H, CH3), 6.94 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.50 (t, 1H, J=8.3 Hz, Ph-H), 7.81 (m, 1H, Ph-H), 7.94 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 8.94 (t, 1H, J=2.2 Hz, Ph-H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C:8]3=[CH:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17])([O-])=O.[Sn](Cl)Cl>CO.O.C(Cl)Cl>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C:8]3=[CH:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2c1cc1n2CCC1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1cc1n2CCC1
Temperature: 60 °C
Yield: 70.6 %

Procedure:
A mixture of methyl 7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 19, 0.160 g) and tin (II) chloride (0.520 g) in methanol (6 mL) and water (0.06 mL) was heated at 60° C. for 8 hours. The resultant mixture was cooled and diluted with DCM and filtered through Celite. The filtrate was washed with 1M aqueous sodium hydroxide solution and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.100 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(NC1(CC(OC)=O)CC(=O)NC1)=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](OCc2ccc(Cl)cc2)CC1
Agent: COC(=O)CC1(NC(=O)OCc2ccccc2)CNC(=O)C1
Product: O=C[C@H]1CC[C@H](OCc2ccc(Cl)cc2)CC1

Procedure:
The ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate (856 mg) obtained in Reference Example 36-1(1) was used and treated by the same techniques as in Reference Example 36-1(2) and (3) to give the titled compound as a yellow oil (388 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH:32]([CH3:34])[N:31]([CH3:35])[CH:30]([CH3:36])[CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:37]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH:30]([CH3:36])[N:31]([CH3:35])[CH:32]([CH3:34])[CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CC(C)N(C)C(C)C2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: Cc1cc(C(=O)N2CC(C)N(C)C(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one was condensed with 3-methyl-5-(3,4,5-trimethyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (br s, 1H, NH), 11.78 (br s, 1H, NH), 9.23 (br s, 1H), 8.33 (s, 1H), 7.72 (dd, J=2.5 & 6.5 Hz, 1H), 7.43 (m, 1H), 7.33-7.38 (m, 2H), 6.58 (m, 1H), 4.19 (m, 2H, CH2), 2.78 (m, 2H), 2.23 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.11 (m, 2H), 1.06 (d, J=6.6 Hz, 6H, 2×CH3). MS 524 [M++1].
Reaction SMILES: O1CCOCC1.[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br.[Br:19][CH2:20][CH2:21][NH2:22].O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C.O>[Br:19][CH2:20][CH2:21][NH:22][C:15](=[O:16])[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a 1,4-dioxane (50 mL) solution comprising benzylchloroformate (17.5729 g; manufactured by Wako Pure Chemical Industries, Ltd.), an aqueous solution of 2-bromoethane amine hydrogen bromide salt-1,4-dioxane [104 mL; solution which was prepared by dissolving 2-bromoethane amine hydrogen bromide salt (21.3617 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) in water (54 mL) and 1,4-dioxane (54 mL)] and an aqueous solution of 2 mol/L-sodium hydroxide (104 mL; manufactured by Kanto Chemical Co., Inc.) were added dropwise simultaneously, and stirred at 0° C. for 2 hours. The reaction solution was added with water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with saturated sodium hydride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=94:6→73:27) to obtain the title compound (19.2014 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH2:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH:29][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCNC(=O)OCc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 42.4 %

Procedure:
Dissolve 4-[1-(2-amino-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.94 mmol; 396.7 mg) in DCM (20 mL) and add DIPEA (1.41 mmol; 0.25 mL) and benzyl chloroformate (0.94 mmol; 0.14 mL). Stir 20 min and wash with saturated sodium bicarbonate, dry over MgSO4, filter and evaporate. Purify over 40 g silica gel with 0-40% EA/DCM to provide the title compound (222 mg; 42%). MS (ES): m/z=557 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12.[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12
Reactant: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 85 °C
Yield: 18.8 %

Procedure:
A stirred suspension of 344 (500 mg, ˜2 mmol), 3,4-difluoronitrobenzene (795 mg, 5 mmol) and cesium carbonate (1.63 g, 5 mmol) in anhydrous DMF (50 ml) was heated at 85° C. under nitrogen for 7 h. The temperature was allowed to cool down to room temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The combined organic phase was concentrated and directly purified twice by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 5/95 to 10/90) to afford title compound 345 (144 mg, 19% yield) as a sticky yellow solid. MS (m/z): 384.0 (M+H)+.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C1COCC1.[BH3-]C#N.[Na+]>CO.Cl[Ti](Cl)(Cl)Cl>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][NH:26][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Add Ti(iPrO)4 (1.70 g, 6.00 mmol) to a suspension-of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), isoamyl amine (314 mg, 3.60 mmol) and THF (10 ml) and stir overnight under a nitrogen atmosphere at ambient temperature. Treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at ambient temperature for three hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). After an additional three hours, quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5%(1N NH3/MeOH)/45% EtOAc/DCM) to obtain 491 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.39 (d, 1H), 7.00 (s, 1H), 6.97-6.94 (m, 2H), 5.87 (br. S, 2H), 4.25 (t, 1H), 3.02 (m, 1H), 2.83 (m, 1H), 2.75 (t, 2H), 2.46 (m, 1H), 1.89 (m, 1H), 1.67 (m, 1H), 1.44 (m, 2H), 0.92 (d, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:5]([O:4][C:2]([NH:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]([OH:16])=[O:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@@H](CCCC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
Benzyl chloroformate (15.5 g) was added dropwise to a stirred mixture of (2S)-2-aminoadipic acid (12 g) and sodium carbonate (39.4 g) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with diethyl ether. The aqueous phase was acidified to pH1 by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give (2S)-2-benzyloxycarbonylaminoadipic acid (21.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:46](=[O:47])[C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=[N:42]2)=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:48]([C:45]2[C:46](=[O:47])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=[CH:43][CH:44]=2)=[O:49])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=3)[N:9]=[C:10]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.213 g, 0.479 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.561 g, 2.40 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.459 g, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.367 g, 2.40 mmol), N-ethyl-N-isopropylpropan-2-amine (0.310 g, 2.40 mmol) and CH2Cl2 (5 mL) were charged in a 50 mL single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until LC-MS shows that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH from 100/1 to 50/1, v/v) to afford product (0.201 g, 63.5%). LRMS (APCI pos): >95% purity, 254 nm, m/e 661 (M+1). 1H NMR (400 MHz, CDCl3 δ 11.75 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.87 (dd, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.42 (s, 1H), 7.28 (m, 3H), 7.13 (m, 3H), 6.75 (m, 2H), 6.20 (d, 1H), 5.56 (s, 2H), 3.83 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O.S(=O)(=O)(O)O>C(O)C>[O:14]=[C:12]([CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCCC(=O)CC(=O)C(=O)OCC
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To refluxing solution of sodium ethoxide (51.2 g, 0.75 mmol) in ethanol (170 ml) was added dropwise over 30 minutes a solution of 2-pentanone (59 g, 0.68 mol) in diethyl oxalate (99 g, 0.68 mol). The resulting turbid yellow mixture was refluxed further for 2 hours, cooled to room temperature, poured over 500 g ice with stirring and adjusted to pH 1-2 with concentrated sulfuric acid (~40 ml). The organic phase was extracted with benzene (3×300 ml), washed once with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, before being filtered, concentrated, and fractionally distilled at 0.1 mm Hg to give 48.2 g (38%) of the title compound as a yellow liquid; b.p. 85°-95° C.
Reaction SMILES: [Br-].[Br-].[Br-].B.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Agent: B
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
Boran tri-bromide in DCM (10 mL) was added to a stirred solution of 7-methoxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (35A: 1.1 g, 4.104 mmol) in DCM (20 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was quenched with methanol and concentrated. The concentrate was partitioned between water and DCM. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (3% methanol in DCM) afforded 850 mg of the product (77% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:8])[N:6]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1noc(C)c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=456.3.