Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:10](OC)(=[O:14])/[CH:11]=[CH:12]/[CH3:13].COC1C=C(OC)C=C(/C=C/CC)C=1C(OC)=O>CO>[O:14]=[C:10]1[CH:3]([C:2]([O:8][CH3:9])=[O:7])[CH:4]([OH:5])[CH2:6][C:12]([CH3:13])=[CH:11]1
Reactant: COC(=O)CC(C)=O
Reactant: C/C=C/C(=O)OC
Agent: CC/C=C/c1cc(OC)cc(OC)c1C(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(=O)C=C(C)CC1O
Yield: 69.6 %

Procedure:
Dissolve sodium metal (3.1 g, 0.134 mol) in dry methanol (200 ml), add in methyl acetoacetate (12.0 g, 0.103 mol) and methyl crotonate (12.4 g, 0.124 mol at room temperature), after finishing the addition, reflux to react for 6h to complete the reaction, then distill out most of the methanol, pour the residue into ice water (200 ml), extract with ethyl acetate (3×50 ml), adjust pH of the aqueous layer to less than 2 with dilute 15% hydrochloric acid, extract again with ethyl acetate (3×50 ml). Pool the organic layer, and wash with saturated brine, dry the solution over anhydrous MgSO4. Filter and evaporate the solution to dryness, redissolve the residue, recrystallize the solution to obtain a white solid as the target product (13.2 g, 70%) with petroleum ether/ethyl acetate and recrystallized. 1H NMR (400 MHz, DMSO-d6): 0.94 (d, J=6.0 Hz, 3H), 2.32 (m, 3H), 3.09 (d, J=9.2 Hz, 1H), 3.63 (s, 3H), 5.21 (s, 1H), 11.37 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[Br:15]Br.O>[N+](C)([O-])=O.[Fe](Cl)(Cl)Cl>[Br:15][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:13])([F:14])[F:1])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 110 °C
Yield: 54.3 %

Procedure:
4-(Trifluoromethoxy)benzoic acid (2 g, 9.70 mmol) and iron(III) chloride (1.574 g, 9.70 mmol) were suspended in nitromethane (20 mL). To this mixture was added bromine (0.497 mL, 9.70 mmol) at 0° C. The solution was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was added to cold water (100 mL) and extracted with ethylacetate (2×100 mL). The organic phase was washed with an aqueous solution of sodium thiosulfate pentahydrate and brine. The organic layer was concentrated and the residue was purified by HPLC to give the title compound as a white solid (1.5 g). LCMS m/z=287.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (d, 1H), 8.06 (d, 1H), 8.29 (s, 1H), 13.47 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[N:34][C:33]([N:36]([CH3:47])[CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:30]1[N:35]=[N:34][C:33]([N:36]([CH3:47])[CH:37]2[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)=[CH:32][CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cc3ccc(O)cc3cc2OCc2ccccc2)OC1(C)C
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 89.3 %

Procedure:
7-(Benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (1.25 g, 2.366 mmol, 89% yield) was prepared from the 7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.45 g, 3.85 mmol) and Intermediate 1-1 (0.75 g, 2.65 mmol) using General method 1-1 for Suzuki coupling. M+1=497.8. 1H NMR (400 MHz, METHANOL-d4) δ 7.91 (s, 1H), 7.76 (d, J=9.54 Hz, 2H), 7.66 (d, J=8.78 Hz, 2H), 7.34-7.40 (m, 2H), 7.31 (s, 2H), 7.18-7.27 (m, 2H), 6.97-7.05 (m, 2H), 6.91 (dd, J=8.78, 2.26 Hz, 1H), 5.18 (m, 3H), 2.92 (s, 3H), 1.60-1.68 (m, 2H), 1.45-1.55 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([CH3:16])[N:15]=[C:5]3[C:4]=2[CH:3]=1.BrC1C=CC2NC(=O)N3N=CN=C3C=2C=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([CH3:16])[N:15]=2)[CH:3]=1
Reactant: Cc1nc2c3cc(Br)ccc3[nH]c(=O)n2n1
Agent: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Product: Cc1n[nH]c(-c2cc(Br)ccc2N)n1
Yield: 98.8 %

Procedure:
As described for example 21c) 9-bromo-2-methyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (28.5 g, 102 mmol), instead of 9-bromo-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (25.5 g, 99%) which was obtained as an off-white solid. MS: m/e=251.0/253.1 [M−H]−.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13].[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13]
Reactant: CCCC(O)C#Cc1ccc(F)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(O)CCc1ccc(F)c(F)c1F
Reaction time: 8 h

Procedure:
After 1-(3-hydroxy-1-hexynyl)-2,3,4-trifluorobenzene was dissolved in ethanol, 5% palladium carbon (50% in water) was added thereto, and stirred for 6 hours at a hydrogen pressure of 0.5 MPa, and the mixture was left to stand overnight. After palladium carbon was removed by filtration, the solvent was evaporated under a reduced pressure to obtain 1-(3-hydroxy-1-hexyl)-2,3,4-trifluorobenzene.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:12])[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[CH:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(=O)[nH]c2nc(OCCCC=O)ccc12
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The crude 4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde from the previous reaction in 1,2-dichloroethane (30 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g, 4.20 mmol), followed by triethylamine (0.90 mL, 6.46 mmol) and sodium triacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with H2O and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methano/vethyl acetate) to afford the title compound (0.97 g, 63% over 2 steps) as a white solid. mp 181–182° C. 1H NMR (CDCl3, 400 MHz): δ 7.57 (br s, 1H), 7.40 (d, 1H), 7.18–7.12 (m, 2H), 7.00–6.94 (m, 1H), 6.38 (d, 1H), 4.23 (t, 2H), 3.16–3.00 (m, 5H), 2.77–2.68 (m, 4H), 2.75–2.56 (m, 1H), 2.52–2.36 (m, 3H), 1.86–1.75 (m, 2H), 1.75–1.64 (m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([NH2:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:66]([NH:73][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:19]2[N:18]=[CH:17][C:8]3[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:7]=3[N:20]=2)=[C:23]([O:31][CH3:32])[CH:24]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCc1ccccc1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccccc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.016 g (0.15 mmole) benzylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 100:0-20:80) to give 0.048 g of N-benzyl-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-35) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]2[S:17][CH2:18][C:19](O)([C:21]([F:24])([F:23])[F:22])[N:20]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C(C)=CC=CC=1C>C(COC)OC>[Br:1][C:2]1[C:3]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a 2 L round bottom flask was charged tert-butyl 5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-ylcarbamate (Intermediate 86, 56.8 g, 128 mmol) and dimethoxyethane (800 mL). The reaction mixture was chilled in an ice-water bath, then trifluoroacetic anhydride (69 mL, 514 mmol) and 2,6-lutidine (133 mL, 1.15 mol) were added simultaneously over 1 h. An orange/yellow solution which resulted was allowed to stir in the ice-water bath for 30 min, then the solution was warmed to room temperature. The orange solution was concentrated under reduced pressure to dryness, and the resulting residue was triturated with methanol. The solid was collected by filtration and washed with more methanol, dried under vacuum overnight, yielding 49 g of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:5]2.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:38][C:39](O)([CH3:41])[CH3:40]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:39]([CH3:41])([CH3:40])[CH3:38])=[O:23])=[CH:5]2
Reactant: O=C(O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
5-(6-Bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 4.00 g, 10.4 mmol) was dissolved in DCM (100 mL). The flask was cooled to 0° C. in an ice/water bath before TFAA (14.7 mL, 104 mmol) was slowly added. After stirring at 0° C. for 1 h, tBuOH (29.9 mL) was gradually added and the reaction mixture was allowed to warm to RT overnight. The mixture was diluted with DCM and sat. Sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. Chromatography (5-100% EtOAc/hexanes) afforded tert-butyl 5-(6-bromo-2-phenylquinolin-3-yl)pentanoate (18, 3.71 g; Yield=81%, LCMS (M+H)=440).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([N+:15]([O-])=O)=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.Cl[Ni]Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([NH2:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc2c(F)c(N)ccc2[nH]1
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (2.1 g, 9.0 mmol) in methanol (50 mL) was added NiCl2 (4.2 g, 18 mmol) and NaBH4 (1.0 g, 27 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indol-5-amine (900 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.80 (brs, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.64 (dd, J=0.9, 2.4 Hz, 1H), 6.23 (s, 1H), 1.38 (s, 9H).
Reaction SMILES: [I-].[CH2:2]([N+:4]1(C)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:3].[CH:12]1(N)CC1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:2]1([N:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[CH2:3][CH2:12]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCN(C2CC2)CC1
Temperature: 78 °C
Yield: 53 %

Procedure:
1-Ethyl-1-methyl-4-oxopiperidinium iodide (Journal of the Chemical Society (1949), 708-15; 15 g, 55.74 mmol) was added to cyclopropylamine (Aldrich; 19.3 mL, 278.69 mmol) in toluene (150 mL). Sodium hydrogen carbonate (469 mg, 5.57 mmol) in water (21 mL) was added and the mixture heated at 78° C. over night. The mixture was cooled and the layers separated. The aqueous layer was extracted (×2) with ethyl acetate and the combined organics washed with brine, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeOH/DCM) gave the title compound (4.1 g, 53%) as a pale brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C2=[C:6]([CH:24]=1)CN(C)CC=C2C1C=CC2N(C)CCOC=2C=1.C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:32]2[CH2:33][CH2:34][CH2:35][CH2:36][NH:31][C:6]=2[CH:24]=1
Reactant: c1ccncc1
Reactant: CN1CC=C(c2ccc3c(c2)OCCN3C)c2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(c1)NCCCC2
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of the dihydrobenzazepine (270 mg, 0.70 mmol) from step F above in pyridine (15 mL) were added potassium carbonate (967 mg, 7.0 mmol) and p-toluenesulfonylhydrazide (672 mg, 3.5 mmol) in batches. The reaction solution was heated under reflux for 24 hours and then cooled to room temperature. The resultant reaction mixture was filtered through Celite. The Celite bed was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue dissolved in ethyl acetate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (3% methanol/dichloromethane) to give the desired 8-bromotetrahydrobenzazepine (176 mg, 65%): 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 6.64 (d, J=8.2 Hz, 2H), 6.60-6.56 (m, 2H), 4.31 (t, J=4.4 Hz, 2H), 4.12 (d, J=9.9 Hz, 1H), 3.83 (br, 1H), 3.69 (d, J=14.2 Hz, 1H), 3.26 (t, J=4.4 Hz, 2H), 3.13-3.10 (m, 1H), 2.95-2.90 (m, 1H), 2.89 (s, 3H), 2.32 (s, 3H), 2.24-2.17 (m, 1H), 2.06-2.04 (m, 1H); ESI MS m/z 387, 389 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:20](CO)[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH2:23][CH2:24][CH2:25][O:26]C2CCCCO2)[N:18]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[N:17]=1)C1C=CC=CC=1.N1C=CC=N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOC(C)=O.C1COCC1.CCOC(C)=O.CCO>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:1][CH:20]3[C:19]([CH2:23][CH2:24][CH2:25][OH:26])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:18]([C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])[N:17]=[C:16]3[C:10]=2[CH:11]=1
Reactant: O=C(N1N=C(c2cc(F)ccc2OCc2ccccc2)C(CO)C1(CCCOC1CCCCO1)c1ccccc1)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N1N=C2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.2 g (10.1 mmol) 3-6 in 200 ml 1:1 EtOAc/EtOH was evacuated under reduced pressure and purged three times with N2 before 200 mg of 10% Pd/C was added. The solution was then evacuated and purged twice with N2, then three times with H2, and stirred at room temperature overnight under a balloon of H2. The mixture was purged with nitrogen, filtered through a pad of celite, and concentrated to give the phenolic pryazole as an amber gum. LC-MS: rt=2.8 min, m/z=441 (M−THP+1). Without further purification, 4.45 g (8.5 mmol) of the phenolic pyrazole was combined with 200 ml of THF, 3.34 g (12.7 mmol) triphenylphosphine and 2.67 ml (17 mmol) DEAD. After stirring for 1 h at room temperature, the solution was dumped into a separatory funnel with 150 ml of EtOAc and successively washed with 50 ml portions of 10% aqueous KHSO4, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography with EtOAc/hexanes to give the THP protected tricycle as colorless gum. LC-MS: rt=3.2 min, m/z=423 (M−THP+1). To a solution of 950 mg (1.9 mmol) of the THP protected tricycle in 100 ml of MeOH was added 1 g (5.3 mmol) of p-toluenesulfonic acid monohydrate, the resulting mixture was stirred at room temperature for 1 h, and concentrated. The residue was purified by reverse phase preparative HPLC using two stacked Waters 40×100 mm PrepPak® cartridges with an 85-5% H2O/CH3CN (0.1% trifluoroacetic acid) 40 minute gradient to give 3-7 as a white solid. Data for 3-7: LC-MS: rt=2.6 min, m/z=423 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:28].[CH3:33][Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:27][CH3:33])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:28]
Reactant: CNCCCCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CNCCCCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A mixture of methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.68 g, 1.45 mmol; Example 1, Step 11) and a solution of trimethylsilyldiazomethane in hexane (2.2 mL, 4.35 mmol; 2M) in dichloromethane-methanol (1.5 & 4.5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated under vacuum to provide the title compound. This was used in the following step without further purification. ES MS M+1=480
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:7]1[S:6][C:5]2[S:1][C:2]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:3][C:4]=2[CH:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2ccsc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc([Sn](C)(C)C)sc2s1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
A solution of thieno[2,3-b]thiophene (2.81 g, 20 mmol) was dissolved in anhydrous THF (100 ml) and cooled to −78° C. under nitrogen. A solution of n-butyllithium (17.6 ml of a 2.5M solution in hexanes, 44 mmol) was added dropwise over 15 min, and the resulting solution was allowed to warm to RT and stirred at that temperature for 16 h. The resulting suspension was cooled to −78° C. and trimethyltin chloride (10.0 g, 50 mmol) was added at once as a solid. The reaction was allowed to warm to RT over 4 h and stirred at that temperature for an additional 20 h. The reaction was quenched by the addition of saturated sodium hydrogen carbonate (100 ml). Ethyl acetate (50 ml) was added and the layers separated. The organic layer was washed-with sodium carbonate (80 ml of a 2M aqeous solution) and brine (80 ml), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was dry loaded onto a 20 g reverse phase silica column and eluted with acetonitrile. The first fraction was collected, concentrated and recrystallised from acetonitrile to afford the product as white flakes (4.15 g, 45%). M/Z cluster centred at 466 (M+). Found C, 31.1; H, 4.4; S,13.8, Calc. for C12H20S2Sn2 C, 30.9; H, 4.3; S, 13.8. 1H NMR (300 MHz, CDCl3) δ 7.23 (s, 2H), 0.38 (s,18H). 13C NMR (75 MHz, CDCl3) δ 152.4, 147.7, 142.7, 126.3, −8.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2C=[CH:13][CH:12]=[CH:11][C:10]=2C(F)(F)F)[C:5]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:4]=2[NH:3]1.[BH4-].[Na+].Cl.C[N:28](C)C=O>>[O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:28]=2)[C:5]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:4]=2[NH:3]1
Reactant: CN(C)C=O
Reactant: O=C1COC(c2ccccc2C(F)(F)F)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C1COC(c2ccccn2)c2cc(Cl)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 2 (9.8 g) in dimethylformamide (80 ml) is gradually added sodium borohydride (1.1 g) at 0° C., and the mixture is stirred at the same temperature for 2 hours, mixed with ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is purified on column chromatography [silica gel/methylene chloride-ethyl acetate (20:3 v/v)] to give crystalline 2-(2-chloroacetyl)amino-2'-trifluoromethylbenzohydrol (4.8 g), which is recrystallized from ether-n-hexane to give pure crystals of Compound 3, mp. 116°-117° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]=[CH:7][N:8]([CH3:10])[CH3:9])[CH3:2].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CC([O-])(C)C.[K+]>>[CH2:1]([O:3][C:4](=[O:11])/[C:5](/[N:6]=[CH:7][N:8]([CH3:10])[CH3:9])=[C:14](\[N:16]([CH3:18])[CH3:17])/[CH3:15])[CH3:2]
Reactant: CCOC(=O)CN=CN(C)C
Reactant: COC(C)(OC)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)/C(N=CN(C)C)=C(/C)N(C)C

Procedure:
A mixture of 4.7 g of N-(dimethylaminomethylene)-glycine-ethyl ester (W. Kantlehner et al., Liebigs Ann Chem. 1980, 344), 8 g of dimethylacetamide-dimethylacetal and 0.4 g of potassium tert-butylate, analogously to 1b), is heated for 8 hours with distilling off of the resulting alcohols. The residue is then fractionated.