Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of 1.8 mL (10.3 mmol) of 3-phenoxybenzyl alcohol (Aldrich Chemical Co.) in 20 mL of CH2Cl2 at room temperature was added 1.5 g of powdered 4 Å molecular sieves and 2.5 g of activated MnO2. The resulting suspension was stirred at room temperature for 0.5 h, at which time an additional 2.5 g of MnO2 was added. After stirring at room temperature for 0.5 h the reaction mixture was filtered through celite to give 1.84 g of the aldehyde 125 as an oil. 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].CCOC(C)=O.CCCCCC>C(O)C.[Pt]>[CH3:18][C:2]([CH3:1])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(C)COC1CCCCO1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)CCC(C)(C)COC1CCCCO1

Procedure:
A mixture of ethyl (2E)-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-enoate (23 g, 90 mmol) and 5% Pt on carbon (3 g, 14.65 mmol) in ethanol (200 mL) was shaken on the Parr under 45 psi of hydrogen for 5 days (complete conversion by TLC: 10% EtOAc/hexane-no UV active spots). The catalyst was filtered off catalyst and the filtrate concentrated. Drying under vacuum gave ethyl 4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentanoate as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.7 (t, 1H), 4.12 (q, 2H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (d, 1H), 3.0, (d, 1H), 2.3 (m, 2H), 1.8 (m, 1H), 1.7-1.5 (m, 6H), 1.9 (s, 3H), 1.88 (s, 3H).
Reaction SMILES: Cl.C[O:3][C:4]1[C:5](OC)=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](CCCCOC4C=C5C(CCC(=O)N5)=CC=4)[CH2:14][CH2:13]3)[C:8]=2[CH:34]=1.[BrH:37]>>[BrH:37].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:8]=2[CH:34]=1
Reactant: COc1cc2onc(C3CCN(CCCCOc4ccc5c(c4)NC(=O)CC5)CC3)c2cc1OC
Agent: Br
Agent: Cl
Product: Oc1ccc2onc(C3CCNCC3)c2c1

Procedure:
2.1 g of 1-acetyl-4-(5,6-dimethoxy-1,2-benzisoxazolyl)piperidine obtained in Example 20 and 25 ml of 48% HBr solution react at reflux for 4 hours, and at room temperature for 10 hours to precipitate a white deposit. The deposit is filtered out and recrystallized in methanol-diethyl ether to obtain 1.0 g of 5-hydroxy-3-(4-piperidinyl)-1,2-benzisoxazole hydrobromide, which is used according to step 4 in Example 13 to obtain 7-[4-(4-(5,6-dihydroxy-benzisoxazolyl)-1-piperidinyl)-n-butoxy]-3,4-dihydro-2(1H)-quinolinone hydrochloride, with a yield of 61%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:30]3[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 45 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 5-methylpyrazin-2-amine (57.4 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (84.3 mg, 877 mol) in added DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 30-70% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-methylpyrazin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72 mg, 158 mol, 45%) as an off white solid. MS (EI/CI) m/z: 456.2 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]=1[CH3:26].[I-].[Na+].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K]>CN(C=O)C>[C:29]1(=[O:39])[N:33]([CH2:2][CH2:3][C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[N:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:5]=2[CH3:26])[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(CCBr)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CCN2C(=O)c3ccccc3C2=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-bromoethyl)-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulphonyl)phenyl]-1H-pyrrole (0.80 mmol) in dry DMF (10 mL) was added sodium iodide (0.80 mmol) and the resulting mixture was stirred at r.t. for 30 min. Potassium phthalimide (0.90 mmol) was then added, and the reaction mixture was heated at 70° C. for 14 h. After cooling the mixture was poured onto crushed ice and extracted with CH2Cl2. The organic phase was thoroughly washed with water to remove the DMF excess, dried and concentrated under reduced pressure. The residue, purified by flash-chromatography (EtOAc/hexane 1:1 v/v), gave the expected compound as an oil which crystallizes on standing. Yellowish needles from EtOAc Mp 198-201° C. (yield 70%) 1H-NMR (CDCl3) δ ppm: 2.04 (s, 3H), 2.86 (t, 2H, J=7.5), 2.98 (s, 3H), 3.88 (t, 2H, J=7.6), 6.42 (s, 1H), 7.07 (m, 6H), 7.61-7.74 (m, 4H), 7.81-7.85 (m, 2H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][NH:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30].N1C=CC=CC=1C1C=CC=CN=1>[Cu-]=O.CN(C=O)C>[CH2:32]([S:29]([N:28]([CH3:27])[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:31])=[O:30])[CH3:33]
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: CCS(=O)(=O)NC
Agent: O=[Cu-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(OS(=O)(=O)c2ccc(C)cc2)c2ncccc12
Temperature: 118 °C
Reaction time: 2 h

Procedure:
In a dried sealable pressure tube flushed with argon was placed methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (2.0 g, 4.57 mmol), prepared as described in Example 2, Step 2), N-methylethanesulfonamide (1.13 g, 9.15 mmol), dry DMF (4 mL) and copper(I) oxide (785 mg, 5.49 mmol) and 2,2′ bipyridyl (857 mg, 5.49 mmol). The tube was capped and heated to 118° C. for 2 hours. The reaction was cooled and filtered through a glass fiber filter, washing with chloroform. The filtrate was diluted with chloroform (about 100 mL total volume) and stirred with an EDTA solution (5 g EDTA in 100 mL water) for two hours or until the aqueous layer became aqua in color and the organic layer became yellow. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was redissolved in 2 mL of DMSO and purified by preparative HPLC (Gilson semi preparative HPLC system using a Waters Nova pak column (10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.025% TfEA)/acetonitrile (0.025% TFA) at 35 mLjmin) and the desired fractions were freeze dried to give the product as a yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2Br)C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2-c2ccccc2)C1
Yield: 80.7 %

Procedure:
A mixture of (S)-tert-butyl 3-(5-bromo-2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.200 g, 0.539 mmol), phenylboronic acid (0.077 g, 0.636 mmol), PdCl2.dPPf (0.019 g, 0.026 mmol) and 1 M aqueous Na2CO3 (1.06 mL, 1.06 mmol) in DME (5.3 mL) was refluxed for 16 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to give the title compound as an oil (0.163 g, 82%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:50][CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:50][CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Temperature: 65 °C
Yield: 88.2 %

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (30 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 3 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 88%). The crude product was used to the next step without purification. MS: (M+H)+=763.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:31]1([C:34]([NH:36][C:37]2[N:54]=[C:40]3[CH:41]=[CH:42][CH:43]=[C:44]([C:45]4[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=4)[N:39]3[N:38]=2)=[O:35])[CH2:33][CH2:32]1.Cl.[CH3:56][C:57]1([CH3:61])[CH2:60][NH:59][CH2:58]1>C(Cl)Cl.O>[CH3:56][C:57]1([CH3:61])[CH2:60][N:59]([C:49]([C:48]2[CH:47]=[CH:46][C:45]([C:44]3[N:39]4[N:38]=[C:37]([NH:36][C:34]([CH:31]5[CH2:33][CH2:32]5)=[O:35])[N:54]=[C:40]4[CH:41]=[CH:42][CH:43]=3)=[CH:53][CH:52]=2)=[O:50])[CH2:58]1
Reactant: CC1(C)CNC1
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)c2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
EDCI (3.59 g, 0.019 mol), HOBt (2.53 g, 0.019 mol) and DIPEA (4.48 mL) were added to a solution of 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (4 g, 0.012 mol) in DCM (150 mL) at room temperature. The resulting mixture was stirred for 10 min at room temperature. Dimethylazetidine hydrochloride salt (1.64 g, 0.013 mol) was added to the solution and the reaction is stirred for 16 hrs. Water was added to the reaction mixture. The organic layer was separated and washed with 2 N NaOH solution, 2N HCl solution and water. The organic phase was dried over MgSO4, filtered and evaporated under vacuum. Purification by flash chromatography (eluant: 1:1 petrol/EtOAc to neat EtOAc) afforded cyclopropanecarboxylic acid{5-[4-(3,3-dimethyl-azetidine-1-carbonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1>O>[OH:3][C:4]1[C:12]([Br:1])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: BrBr
Solvent: O
Product: O=C(O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Bromine (4.2 mL, 81.4 mmol) was added dropwise to the suspension of 6-hydroxynicotinic acid Compound 116a (8.00 g, 57.6 mmol) in water (30 mL) at 4° C. After the completion of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. Saturated Na2SO5 was added slowly to the stirred mixture until the brown mixture became white. The solid was collected through filtration, washed with water, and dried under vacuum overnight to give 12.17 g (97%) of 6-hydroxy-5-bromonicotinic acid as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ12.95 (brs, 1H), 12.55 (brs, 1H), 8.16 (s, 1H), 8.04 (s, 1H). Quinoline (1.0 mL, 8.47 mmol) was slowly added to the solution of POCl3 (2.0 mL, 21.5 mmol), followed by 6-hydroxy-5-bromonicotinic acid (3.92 g, 18.0 mmol) at room temperature. After heating at 120° C. for 2 h, the reaction was quenched by addition of water dropwise at 10° C. After the mixture was cooled at 4° C. for a few hours, the solid was collected through filtration, washed with water, and dried under vacuum overnight to give 3.68 g (87%) of Compound 116b as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ8.86 (s, 1H), 8.55 (s, 1H); MS (ES) m/z: 236 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:29]=[CH:30][N:31]=2)[CH:5]=[C:6]([C:17]([N:19]2[CH2:22][C:21]([CH:24]([N+:26]([O-])=O)[CH3:25])([OH:23])[CH2:20]2)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:26][CH:24]([C:21]1([OH:23])[CH2:22][N:19]([C:17]([C:6]2[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:2]([Cl:1])[C:3]3[N:4]([CH:29]=[CH:30][N:31]=3)[CH:5]=2)=[O:18])[CH2:20]1)[CH3:25]
Reactant: CC([N+](=O)[O-])C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol (195 mg 0.35 mmol) in tetrahydrofuran/water (5 mL, 4:1) was added iron powder (193 mg, 3.5 mmol) and ammonium formate (438 mg, 7.0 mmol). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature and filtered through a pad of celite. The celite was washed three times with boiling ethanol (20 mL). The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The precipitate which formed was filtered through a pad a celite and the filtrate was partitioned with water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow residue which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford mg, 0.05 mmol (15%) of 3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol acetate salt as a white solid. 1H NMR (400 MHz, DMSO): 8.79 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.54-6.48 (m, 1H), 4.24-4.13 (m, 1H), 3.98-3.84 (m, 2H), 3.61-3.56 (m, 1H), 2.83 (q, 1H), 0.92-0.88 (m, 3H); MS (EI) for C19H18ClFIN5O2: 530 (MH+).
Reaction SMILES: Br[C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[Cl-].[NH4+]>C1COCC1>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([C:20]2([OH:19])[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]2)=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3c4c(cccc24)CC3)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromoacenaphthylene (1.00 g, 4.29 mmol) in dry THF (20 mL), under nitrogen at −78° C., was added a solution of n-butyllithium (2.5M in hexanes) (1.89 mL, 4.72 mmol) over a period of 30 min. The resulting deep red solution was left to stir for a further 30 minutes at −78° C. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.94 g, 4.72 mmol) in dry THF (10 mL) was then added over 30 min. After 2.5 h a cooled solution of saturated ammonium chloride (30 mL) was added, the reaction mixture allowed to warm to room temperature and then extracted with diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to yield a thick, yellowish tan oil. This oil was purified by flash chromatography on silica, eluting with a methanol/dichloromethane gradient, to yield tert-butyl 4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate as a sticky yellow residue.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:19]=[C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C1CNCCN1
Product: CCCCCCCCCCCC(=O)N1CCN(C(=O)CCCCCCCCCCC)CC1

Procedure:
Example 1 was repeated using piperazine and two equivalents of dodecanoyl chloride to obtain 1,4-bis(1-oxododecyl)-piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:38]C)(=[O:37])[C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:38])=[O:37]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)c1ccccc1
Product: O=C(O)[C@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)c1ccccc1

Procedure:
Prepared from 2,6-dibromo-4-(6-bromo-benzo[b]naphtho [2,3-d]thiophen-11 -yl)-phenol (Example 21) and commercially avialable methly (s)-(+)-mandelate. White solid: mp 135-137° C.: MS (FAB-): [M-H]-, 693; Anal. Calc. for C3OH17Br3O3S: C, 51.68, H, 2.46, N, 0.00. Found: C 51.57, H, 2.89, N, 0.14.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[C:12]=2[CH:16]2CC2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([C@H]1CC[C@H](OC2C(C)=C3C(=CC=2)C=C([C@]2(C)COC(=O)N2)C=C3)CC1)(C)(C)C>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[C:12]=2[CH3:16])[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Agent: Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@]3(C)COC(=O)N3)ccc12
Product: Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@@](C)(N)CO)ccc12

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol (Example 215) in 64% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=353.44 [M-16]+. 1H NMR (MeOD) δ: 8.06 (d, J=9.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.58 (dd, J=9.0, 2.3 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 4.21-4.31 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.53 (s, 3H), 2.17-2.26 (m, 2H), 1.87-1.95 (m, 2H), 1.80 (s, 3H), 1.42-1.56 (m, 2H), 1.10-1.28 (m, 3H), 0.93 (s, 9H)
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28](F)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10].C(N(CC)CC)C>CS(C)=O>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28]([N:5]4[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)C1
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
Under nitrogen atmosphere at 140 to 150° C., a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidin (86 μl, 679 μmol) was added to a dimethyl sulfoxide (10 ml) solution of N-(1-acetylpyrrolidin-3-yl)-4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-206) (238 mg, 566 μmol) and triethylamine (103 μl, 736 μmol), followed by stirring at the same temperature for 45 minutes. After cooling, the solvent was evaporated away under reduced pressure, the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, then the aqueous layer was extracted with ethyl acetate. Next, saturated sodium hydrogencarbonate water was added to the aqueous layer, followed by extraction with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (153 mg, 53%) as an amorphous substance.