Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:56][N:57]1[CH:61]=[C:60]([CH2:62]O)[N:59]=[N:58]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:62][C:60]1[N:59]=[N:58][N:57]([CH3:56])[CH:61]=1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: Cn1cc(CO)nn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(COc2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)nn1

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol), resin-bound triphenylphosphine (180 mg of 3 mmol/g resin, 5.4 mmol), diisopropylazodicarboxylate (76.8 μL, 78.8 mg, 0.40 mmol) and 1-methyl-1H-1,2,3-triazole-4-methanol (prepared as described in WO 0023449, 22.0 mg, 0.20 mmol) were stirred together in THF (3 mL) at room temperature overnight. The mixture was filtered, and the filtrate was diluted with dichloromethane (15 mL), was washed with 1 N sodium hydroxide (2×10 mL), was dried over magnesium sulfate and was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 2.5% methanol in dichloromethane, affording 5-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine as a colourless solid, which was recrystallised from ethyl acetate/isohexane (26.7 mg, 41%). δH (360 MHz, CDCl3) 4.13 (3H, s), 5.35 (2H, s), 7.03-7.07 (1H, m), 7.25-7.31 (1H, m), 7.38 (1H, dd, J 2.1 and 7.7), 7.54 (1H, d, J 4.6), 7.70 (1H, s), 7.86 (1H, d, J 8.8), 8.53 (1H, d, J 8.8), 9.26 (1H, d, J 4.2). m/z (ES+) 404 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Br[CH2:39][C:40]([N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C(C)(C)CCCC3(C)C)c(F)c2)c1
Yield: 33.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].Cl.O.[OH-].[Na+]>COC(C)(C)C>[CH3:3][C:2]([NH2:14])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(N)c1ccc(C(F)(F)F)nc1
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
Heat a mixture of N-[1-Methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (93.5 moles, 19.1 kg), concentrated hydrochloric acid (805.9 moles; 66.2 L; 79.4 kg), and water (79.4 L; 79.4 kg) to 95-100° C. with stirring under nitrogen for 24 hours. Cool the reaction mixture to 20-35° C. and observe completion of the reaction by HPLC. Cool the reaction vessel to 10-20° C. and add tert-butyl methyl ether (105.4 L; 78.0 kg). Separate the phases, and discard the organic layer. Add 15% sodium hydroxide (910.9 moles; 205 L; 242.9 kg) to the aqueous phase and observe a pH of 9.5-10.5. Extract the aqueous layer with ethyl acetate (3×89 mL; 3×80.0 kg), combine the organic layers, and discard the aqueous phase. Concentrate the solution to approximately 2 volumes, add tert-butyl methyl ether (174 L; 129.1 kg), and concentrate the solution to approximately 2 volumes. Dilute the reaction vessel with n-heptane (168 L; 115.0 kg), concentrate the solution to approximately 2 volumes, and dilute with additional n-heptane (30 L, 20.7 kg). Cool the contents of the reaction mixture to 0-5° C. and stir the mixture for 2 hours at 0-5° C. Filter and dry the resultant solids under vacuum at 35-45° C. to afford the titled compound (14.19 kg; 74.3%, based on HPLC) as a 97.9% pure tan powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:19]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (1 g) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (0.63 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g) This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[Na+].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].Cl>O.CO>[ClH:1].[CH:14]([CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1)([CH3:15])[CH3:13]
Reactant: CC(C)C=O
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1NCCc2[nH]cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Histamine dihydrochloride (61.9 g, 336 mmol) was dissolved in a solution of NaOH (33.6 g, 841 mmol) in water (125 mL) and MeOH (500 mL), and isobutyraldehyde (61.4 mL, 672 mmol) was added. The reaction mixture was heated under reflux at 80° C. for 24 h, cooled to room temperature, the pH was adjusted to 7 with 1 M aq HCl solution (250 mL) and the solvents were removed in vacuo. The residue was dissolved in warm MeOH (300 mL), allowed to stand for 1 h, filtered and the solvents were removed in vacuo. The residue was stirred in MeOH (50 mL) and acetone (400 mL) for 2 h and was cooled to 4° C. for 2 h. The resulting precipitate was filtered and washed with acetone (100 mL) to give 4-isopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride (33.0 g, 48.7%) as a white solid.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+].[Na+].S(O)(O)(=O)=O.[NH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[NH:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[NH:21]>O>[C:1](=[O:2])([OH:4])[OH:3].[NH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[NH:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[NH:31].[C:1](=[O:2])([OH:4])[OH:3].[C:1](=[O:2])([OH:4])[OH:3].[NH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[NH:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[NH:31]
Reactant: O=C([O-])[O-]
Agent: N=C(N)NCCCCCCNCCCCCCNC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)O

Procedure:
At 70° C., a solution of 170 g of sodium carbonate in 340 ml of hot water is added to 100 g of N,N'"-(iminodi-6,1-hexanediyl)-bis-guanidine sulfate (British No. 1,114,155) dissolved in 500 ml of water. The mixture is cooled with ice and filtered. The residue is dried under reduced pressure. There is obtained 53 g of N,N'"-(iminodi-6,1-hexanediyl)-bis-guanidine sesquicarbonate of melting point 171°-175° C.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][O:8][CH2:9][C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:25]C)[C:14]([O:23]C)=[N:15]2)(C)(C)C>Br.C(O)(=O)C.C(OCC)C>[O:23]=[C:14]1[C:13](=[O:25])[NH:12][C:11]2[C:16](=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:10]=2[CH2:9][O:8][CH2:7][C:6]([OH:27])=[O:5])[NH:15]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(COCC(=O)OC(C)(C)C)c2nc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)COCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
270 mg (0.711 mmol) of 2-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethoxy)-acetic acid tert-butyl ester are dissolved in 6 ml of an approximately 16% hydrogen bromide solution in acetic acid and the solution is stirred at room temperature for 20 hours. The reaction mixture is diluted with diethyl ether and the solid is filtered off, washed with diethyl ether and dried. The title compound is obtained in the form of a solid (m.p.>300° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([C:18](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 5.84 g (13.1 mmol) of (S)-N-[(1-Benzyl)-4-(R)-(3-thienyl)-3-(S)-pyrrolidinylcarbonyl]-4-benzyl-2-oxazolidinone (Step 2) in 60 mL of THF at 0° C. was added 15.7 mL (15.7 mmol) of a solution of LiAlH4 (1.0 M in ether). The solution was stirred at room temperature for 3 h, then was quenched by addition of 5N NaOH solution. The mixture was diluted with ether and the organic fraction was washed twice with 5N NaOH solution. The combined organic fractions were dried over Na2SO4, filtered, and the filtrate concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:6) to afford 3.22 g of the title compound. 1H NMR (CDCl3) δ7.33-7.34 (m, 4H), 7.26-7.30 (m, 2H), 7.02-7.04 (m, 2H), 3.77 (d of d, 1H, J=10.3, 4.3 Hz), 3.68 (d of d, 1H, J=10.1, 5.0 Hz); Mass spectrum (ESI) m/e=274 (M+1); [α]D=−13.6 (c.=1.60, CHCl3).
Reaction SMILES: [C:1]([N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:1]([N:20]([CH2:24][CH2:25][O:26][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH2:21][CH2:22][O:23][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
From N-trityldiethanolamine and p-toluenesulfonyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:27]3=[CH:28][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([O:32]C)=[O:31])=[N:14][N:13]=4)=[CH:6][CH:5]=2)[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([C:3]1[C:4]2[C:27]3=[CH:28][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[O:38][C:15]([NH:16][C@@H:17]([CH:35]([CH3:37])[CH3:36])[C:18](=[O:34])[N:19]5[CH2:29][C@H:22]([O:23][C:24]3=[N:25][CH:26]=1)[CH2:21][C@H:20]5[C:30]([OH:32])=[O:31])=[N:14][N:13]=4)=[CH:6][CH:5]=2)[CH3:2]
Reactant: CCc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R,5S,8S)-22-ethyl-8-isopropyl-7-oxo-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylate (from Step 2) in THF/H2O (1/1 v/v) was added LiOH (4 eq). The resulting reaction mixture was stirred at RT for 2 h and then treated with 1N aq. HCl until pH=2 was reached. The aqueous phase was extracted with EtOAc, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a white solid. MS (ES+) C27H33N5O5 requires: 507. Found: 508 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15].[CH3:21][NH:22][CH3:23]>C(COC)OC>[CH3:21][N:22]([CH3:23])[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Reactant: CNC
Solvent: COCCOC
Product: CCn1c(C)nc2cc(C(F)(F)F)c(N(C)C)c([N+](=O)[O-])c21
Temperature: 125 °C

Procedure:
A glass reaction tube was charged with 5.0g. (0.016 mole) of 6-chloro-1-ethyl-2-methyl-7-nitro-5-trifluoromethylbenzimidazole, 20 ml. of dimethoxyethane and 15 ml. of dimethylamine and then sealed. The sealed tube was maintained at 125°C. for 16 days and then opened. The contents were evaporated to dryness and the residue extracted with hot hexane, from which crystallized 3.1g. of the desired product m.p. 111°-115°C. after recrystallization from hexane.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[F:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[K+].C(O)CCC>CCOC(C)=O.O>[F:17][C:18]1[C:23]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1

Procedure:
To a round bottom flask, under a reflux condenser, was added 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.0 g, 3.5 mmol), 2-fluoropyridin-3-ylboronic acid (0.75 g, 5.3 mmol), potassium acetate (1.0 g, 11 mmol), 1-butanol (50 mL) and DI water (10 mL). The mixture was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2(P-tert-Bu2Ph)2 (0.026 g, 0.042 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 45 min (complete by TLC, 80% EtOAc/hex).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Sn](C)(C)C)[N:8]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:6]=1[Cl:19])(=[O:3])[CH3:2].[F:20][C:21]1[C:27]([F:28])=[C:26](I)[C:25]([F:30])=[CH:24][C:22]=1[NH2:23].[F-].[K+]>CN(C=O)C.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.[Cu]I>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:26]2[C:25]([F:30])=[CH:24][C:22]([NH2:23])=[C:21]([F:20])[C:27]=2[F:28])[N:8]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:6]=1[Cl:19])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc([Sn](C)(C)C)cc(NC(C)=O)c1Cl
Reactant: Nc1cc(F)c(I)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2c(F)cc(N)c(F)c2F)cc(NC(C)=O)c1Cl
Temperature: 20 °C
Yield: 53.2 %

Procedure:
A suspension of methyl 4-acetamido-3-chloro-6-(trimethylstannyl)picolinate (Head K) (0.502 g, 1.409 mmol, 1.0 eq), 2,3,5-trifluoro-4-iodoaniline (0.5 g, 1.831 mmol, 1.3 eq), bis(triphenylphosphine)palladium(II) chloride (0.098 g, 0.1401 mmol, 0.1 eq) and CuI (26 mg, 0.1401 mmol, 0.1 eq) in dry DMF (3 mL) was irradiated with microwave at 120° C. for 1 h. Reaction mixture was cooled to 20° C. and stirred with aqueous KF solution (20 mL) for 15 m and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anh. Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified on silica gel (60-120) using a gradient from 0-30% EtOAc in hexanes yielded the title compound as a brown solid (280 mg, 44.8%): 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.32 (s, 1H), 6.51-6.46 (m, 1H), 6.22 (brs, 2H), 3.92 (s, 3H), 2.23 (s, 3H); ESIMS m/z 376 ([M+3H]+).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]2[C:3]=1[C:4]([NH2:18])=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:4]1[C:3]2[C:7](=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:2]=2[C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=3)=[O:35])=[CH:31][CH:32]=2)[NH:6][N:5]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: Nc1n[nH]c2c(CN3CCOCC3)ccc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2c(CN3CCOCC3)ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c12
Temperature: 145 °C
Yield: 49 %

Procedure:
A solution of Example 15F (80 mg, 0.22 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea (108 mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treated with a solution of Na2CO3 (58 mg) in water (1 mL), degassed with nitrogen for 2 minutes, treated with Pd(PPh3)4 (13 mg, 0.011 mmol), and degassed with nitrogen for another 2 minutes. The vial was capped and heated to 140-150° C. for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300 W). The reaction was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC using the conditions in Example 15H to provide 55 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53 (t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s, 1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]([CH3:30])=[CH2:29].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([CH3:30])[CH2:29][O:41]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Solvent: ClCCl
Product: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1
Yield: 14.8 %

Procedure:
A solution of 3.0 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[ (2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.4 g of m-chloroperbenzoic acid for 210 minutes. The solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo to give an oil which solidifies on standing. Recrystallization from acetone-hexane gives 1.94 g as a first crop, and 820 mg as a second crop. Recrystallization of 600 mg of crop 1 from acetone-hexane gives 460 mg of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-methyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione, melting point 193°-236°C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([F:48])=[CH:21][C:22]=1[C:23]1[C:28]2[S:29][C:30]([C:32]3[C:37]([F:38])=[CH:36][N:35]=[C:34]([NH:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][NH:44][C:43]4=[O:47])[N:33]=3)=[CH:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)C)(C)(C)C>ClCCl>[F:38][C:37]1[C:32]([C:30]2[S:29][C:28]3[C:23]([C:22]4[C:17]([CH2:16][NH:14][CH3:13])=[CH:18][N:19]=[C:20]([F:48])[CH:21]=4)=[CH:24][CH:25]=[CH:26][C:27]=3[CH:31]=2)=[N:33][C:34]([NH:39][CH2:40][CH2:41][N:42]2[CH:46]=[CH:45][NH:44][C:43]2=[O:47])=[N:35][CH:36]=1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Add trifluoro-acetic acid (1 mL) to a solution of [6-fluoro-4-(2-{5-fluoro-2-[2-(2-oxo-2,3-dihydro-imidazol-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (280 mg, 0.47 mmol) in dichloromethane (1 mL). Stir for 1 hour and remove solvent on a rotovap. Wash with saturated NaHCO3 and extract in dichloromethane, wash with saturated aqueous sodium chloride, dry over Na2SO4, and filter. Remove solvent on a rotovap to obtain the solid and dry under vacuum to afford the product (196 mg). MS (ES) m/z 494 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][NH2:30]>C(OCC)(=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][NH2:30])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: NN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)NN)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-tert-butyl benzoic acid (0.2 g, 1.2 mmol in 10 mL of dry THF) cooled to 0° C. and treated with N-methyl-morpholine (1.6 mL, 14.6 mmol) as well as isobutyl chloroformate (1.7 mL, 1.3 mmol). Then the mixture was stirred for 10 minutes at 0° C. After hydrazine (0.6 g, 3.6 mmol) was added to the reaction mixture, it was stirred 3 hours at 25° C. The reaction was then diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution as well as brine, and concentrated in vacuum. The crude material was chromatographed on silica gel eluting with hexanes/ethyl acetate=2:1 to give 4-tert-butyl-benzoic acid hydrazide.