Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[C:17]([O:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CO.C(O)(=O)C.ClCCl.[C].[Pd]>[C:28]([O:27][C:25]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:26])([CH3:29])([CH3:30])[CH3:31].[C:25]([O:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26]
Reactant: c1ccc(CN2CCc3occc3C2)cc1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2occc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 15.023 g (70.438 mmol) of 5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 100 ml of methanol, 2 ml of acetic acid was added, followed by hydrogenation over 5 g of 10% palladium-carbon (50% hydrated) at room temperature at atmospheric pressure for 8 hours. The mixture was filtered using Celite to remove the catalyst; the Celite was washed with methanol 3 times. The combined methanol solution was evaporated under reduced pressure. The resulting residue (crude 4,5,6,7-tetrahydrofuro[3,2-c]pyridine) was dissolved in 100 ml of dichloromethane. To this solution, a solution of 15.4 g (70.4 mmol) of di-tert-butyl dicarbonate in 50 ml of dichloromethane was added dropwise at room temperature, followed by stirring for 0.5 hours. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to yield 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine as a mixture with di-tert-butyl dicarbonate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31].O>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([CH:12]([OH:17])[C:13]([F:15])([F:16])[F:14])[C:3]([O:18][CH3:19])=[C:2]([NH:1][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of crude product (0.397 g) containing 1-(3-amino-5-tert-butyl-2-methoxyphenyl)-2,2,2-trifluoroethanol and N,N-diisopropylethylamine (0.374 mL, 2.14 mmol) in THF (4.77 mL) was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (0.217 mL, 1.57 mmol) was added thereto, followed by stirring the mixture for 10 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0-75/25) to obtain 0.622 g of the captioned compound (96% yield in 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2cccs2)=C1c1ccc(Cl)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2cccs2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 3.35 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-thienyl)-2(5H)-furanone, 0.70 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 7 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 1.46 g of 5-(4-chloro-phenyl)-6-methyl-4-(2-thienyl)-2H-pyridazin-3-one.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([OH:16])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)c1c(O)cccc1CC=C
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1c(CC=C)cccc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
To a solution of allyl 6-allyl-2-hydroxybenzoate (v) (1.2 g, 5.5 mmol) in acetone (12 mL) was added K2CO3 (0.84 g, 6.05 mmol) and Mel (1.04 mL, 16.5 mmol) and the mixture was stirred for 40 h at rt. After filtration of the mixture through a short plug of silicagel, the filtrate was concentrated in vacuo and the residue purified by FC (3% Et2O/pentane) to give 1.25 of allyl 6-allyl-2-methoxybenzoate (via) (98%) as a colorless oil. via: IR 2918, 2850, 1733, 1715, 1585, 1363, 1244, 1223, 914, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (1H, app.t, J=8.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.79 (1H, d, J=8.4 Hz), 5.97-6.06 (1H, m), 5.86-5.96 (1H, m), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.4 Hz), 5.05 (1H, br d, J=16.8 Hz), 5.04 (1H, br d, J=I0.0 Hz), 4.82 (2H, br d, J=6.0 Hz), 3.82 (3H, s), 3.36 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 138.7, 136.4, 132.1, 130.6, 123.6, 121.8, 118.8, 116.5, 109.2, 66.0, 56.1, 37.9; MS (EI) 232 (M+, 18), 191 (28), 175 (34), (147 (50), 132 (100), 115 (58). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.10; H, 6.87. vib (MOM): IR 2956, 2928, 2853, 1732, 1636, 1589, 1466, 1256, 1153, 1031, 919 cm]; 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J=7.6, 8.4 Hz), 7.01 (1H, d, J=7.6 Hz), 6.88 (1H, d, J=8.4 Hz), 6.01 (1H, ddt, J=5.6, 10.0, 17.2 Hz), 5.90 (1H, ddt, J=6.8, 10.4, 16.8 Hz), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.0 Hz), 5.17 (2H, s), 5.06 (1H, br d, J=16.8 Hz), 5.05 (1H, br d, J=10.4 Hz), 4.81 (2H, d, J=5.6 Hz), 3.46 (3H, s), 3.37 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 154.2, 138.8, 136.5, 132.2, 130.7, 124.7, 123.0, 118.9, 116.6, 112.9, 94.9, 66.0, 56.4, 37.8. HRMS Calcd for C15H18O4Li (MLi+): 269.1365. Found: 269.1371.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.Cl.[OH-].[Na+]>Cl.ClCCl>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:11][CH2:10][CH2:9][C:6]1[C@@H:7]2[CH2:8][C@H:3]([CH2:4][CH:5]=1)[C:2]2([CH3:12])[CH3:1]
Reactant: C1=COCCC1
Reactant: CC1(C)[C@H]2CC=C(CCO)[C@@H]1C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)[C@H]2CC=C(CCOC3CCCCO3)[C@@H]1C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A solution of 2-{(1R,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl}ethanol (61.6 g) in a minimum of dichloromethane (20 ml) was acidified by treatment with concentrated hydrochloric acid (2 drops). The solution was then treated with 2,3-dihydropyran (56 g), dropwise, at such a rate that the temperature rose to 60° C. and remained at 60° C. During the addition of the 2,3-dihydropyran the acidic nature of the mixture was maintained by the addition of one or more further small quantities of concentrated hydrochloric acid. The mixture was stirred at 60° C. for a further period of 3 hours, and was then added dropwise to a vigorously stirred, ice-cooled, aqueous sodium hydroxide solution (2 N; 91 ml). The resulting mixture was extracted with diethyl ether and the ethereal extract was dried over sodium sulphate, and concentrated and distilled in vacuo, to give 2-{(1R,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl}ethyl tetrahydropyran- 2-yl ether (74 g), b.p. 160°-167° C./14 mmHg [νmax (liquid film): 978, 998, 1038 cm-1. N.M.R. (10% w/v solution in deuterochloroform): multiplets at 5.3δ, 4.55δ, 2.25δ, 1.6δ, broad multiplet at 3.6δ, singlets at 1.3δ, 0.83δ. C16H26O2 requires C, 76.75%; H, 10.47%; found C, 76.75%; H, 10.6%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]=1[CH3:26])=[O:9]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc(Br)ccc1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a solution of 5-bromo-2-(trifluoromethyl)benzoic acid (1.00 g, 0.00371 mol) in CH2Cl2 (15 mL) at room temperature are added methyl 4-amino-3,5-dimethylbenzoate (0.46 g, 0.00260 mol, see preparation 12) and triethylamine (1.10 ml, 0.00743 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 6.00 ml, 0.00929 mol) is added via syringe and stirred at room temperature. After 14 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) with 10-15% EtOAc to give the title compound as an off-white solid (0.45 g, 27.67%).
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[CH3:7][C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=1>O>[Br:1][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[N:13]=1
Reactant: Cc1cccc(CO)n1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cccc(CBr)n1

Procedure:
To a flask containing a mixture of 15 ml of 48% hydrobromic acid and 11 ml of sulfuric acid was added 5 g of 6-methyl-2-pyridinemethanol dropwise under nitrogen. The mixture was heated to 90 C for 4 hours, and poured into 25 ml of water. After neutralization with sodium carbonate, the product was extracted with 100 ml ethyl acetate and washed with 30 ml of water. Following solvent removal, the product was purified by silica gel chromatography using 25% ethyl acetate in hexane, resulting in 6.3 g of a pink oil which solidified on storage at −5 C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:35])([CH:32]([F:34])[F:33])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]([F:35])([F:19])[CH:32]([F:34])[F:33])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [example 30a), b)] following procedure I yielded the title compound as a white solid. MS (ISP): m/z=495.2 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly in small portions over a period of 20 min. to a suspension of sodium hydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h, till the formation of clear solution. Then a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (Intermediate A, 5 g, 0.01968), in dry DMSO (20 mL) was added slowly dropwise, stirred at rt for 30 mins. After completion of reaction, checked by TLC, the reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2×150 mL). Combined organic extracts were washed with ice water (2×150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as a green liquid. The crude is carried to next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]3[CH2:21][O:20][CH2:19]3)[N:13]([CH3:23])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][C:30]=1[N:45]1[CH2:56][CH2:55][C:54]2[C:53]3[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50][C:49]=3[S:48][C:47]=2[C:46]1=[O:59])(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.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.Cl[Pd]Cl.[Fe+2]>[C:24]([O:27][CH2:28][C:29]1[C:34]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH2:16][N:17]([CH3:22])[CH:18]4[CH2:21][O:20][CH2:19]4)[N:13]([CH3:23])[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:33][C:32]([F:44])=[CH:31][C:30]=1[N:45]1[CH2:56][CH2:55][C:54]2[C:53]3[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50][C:49]=3[S:48][C:47]=2[C:46]1=[O:59])(=[O:26])[CH3:25]
Reactant: CN(Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C)C1COC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN(C)C4COC4)n(C)n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 67 %

Procedure:
A sealed tube was charged with the mixture of 5-bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 320d (250 mg, 0.65 mmol), (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b (334 mg, 0.65 mmol), Pd(dppf)Cl2 (55 mg, 0.07 mmol), K3PO4.3H2O(345 mg, 1.3 mmol), and NaOAc (105 mg, 1.3 mmol) in CH3CN (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 322a as a yellow solid (300 mg, 56%). MS: [M+H]+ 689.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][CH2:19][C:20]([NH2:22])=[O:21].C([Al](CC)CC)C>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:18]([CH2:19][C:20]([NH2:22])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCC(N)=O
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CO
Product: NC(=O)Cn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 85 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2.5 g, 0.013 mol), methanol (50 mL, 1 mol), glycinamide hydrochloride (3.0 g, 0.027 mol) and triethylaluminum (4.4 mL, 0.033 mol) and heated at 85° C. for 3 hours. The solvent was removed under reduced pressure to get the product as a yellow solid. MS m/z=248.2 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:21][O:20][C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: COc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc(N2CCNCC2)n1

Procedure:
Prepared in analogy to example 4.10 (c) from 4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 196.4 (MH+, 100%)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[Li]CCCC.CCCCCC.B(OC)(OC)OC.FC(F)(F)S(O[C:31]1[C:40]2[C:35](=[CH:36][C:37]([CH3:41])=[CH:38][CH:39]=2)[O:34][C:33](=[O:42])[CH:32]=1)(=O)=O>CCOCC.C1COCC1.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>[O:4]1[CH:5]=[CH:6][C:2]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[O:34][C:33](=[O:42])[CH:32]=2)=[CH:3]1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc2c1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromofuran (2.36 g, 16.1 mmol) in dry Et2O (146 ml) was added at -78° C. n-BuLi in hexane (6.42 ml, 16.1 mmol, 2.5M). The resulting solution was stirred for 20 min., then (MeO)3B (1.82 ml, 16.1 mmol) was added dropwise and after 20 min., a mixture of the triflate from Step 1 (4.50 g, 14.6 mmol) and (PPh3)4Pd (1.69 g, 1.46 mmol) in THF (60 ml) and H2O (10 ml) was added. The cooling bath was removed and the resulting mixture was heated to 65° C. for 1.75 h. The solvent was evaporated and H2O was added followed by extraction with EtOAc (3×50 ml). The combined organic phases were washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatography (toluene: (2-10% EtOAc)) gave 2.5 g of the title compound, m.p. 160°-162° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=2)[N:3]=1.[CH:23]([B-](F)(F)F)=[CH2:24].[K+].C(N(CC)CC)C>CC(O)C.C1COCC1>[CH3:22][O:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:23]=[CH2:24])=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1nn(Cc2cccc(OC)n2)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To 3-iodo-1-((6-methoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (2.65 g, 6.46 mmol) in IPA/THF (40 mL/10 mL) was added potassium vinyltrifluoroborate (1.30 g, 9.69 mmol), triethylamine (1.31 g, 12.9 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.264 g, 0.323 mmol). The reaction mixture was heated to reflux and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated to remove solvent. The residue was dissolved with EtOAc (100 mL) and washed with saturated NH4Cl, H2O and brine. The solution was dried (Na2SO4) and concentrated to provide the desired product (1.89 g).
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:19]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[F:20][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:28])=[CH:19][C:6]2[C:7]3[N:8]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: C#CC(C)(O)c1ccccn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: CC(O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)c1ccccn1
Yield: 6.3 %

Procedure:
9-fluoro-10-(3-hydroxy-3-(pyridin-2-yl)but-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-(2-pyridyl)but-3-yn-2-ol to afford 7.5 mg of the titled compound (6.3% yield). M+1=403.1. 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=7.6 Hz, 1H), 8.58 (d, J=4.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.82 (s, 1H), 737 (d, J=7.9 Hz, 1H), 7.57 (br s, 1H), 7.38-7.32 (m, 1H), 7.29 (d, J=10.1 Hz, 1H), 7.11 (br s, 1H), 6.47 (s, 1H), 4.94-4.87 (m, 1H), 3.75-3.67 (m, 1H), 3.14-3.03 (m, 2H), 1.83 (s, 3H), 1.71-1.64 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:5][CH2:6][CH2:7]O)[CH3:2].S(Cl)([Cl:15])=O>>[CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:5][CH2:6][CH2:7][Cl:15])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(CC)COCCO
Product: CCCCC(CC)COCCCl
Yield: 94.2 %

Procedure:
500 g (2.81 mol) of 2-(2-ethylhexyloxy)ethanol and 500 g of thionyl chloride were placed in a 2-liter four-neck flask and refluxed with heat for 2 hours. Subsequently, a distillation under reduced pressure was conducted to obtain 510 g of 2-(2-ethylhexyloxy)ethylchloride as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([OH:15])[CH2:5][P:6]([CH2:11][CH2:12][CH2:13][CH3:14])(=[O:10])[O:7]CC.[OH-].[Na+:24]>C(O)C.O>[NH2:2][CH2:3][C:4]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)([OH:15])[CH2:5][P:6]([CH2:11][CH2:12][CH2:13][CH3:14])(=[O:7])[O-:10].[Na+:24]
Reactant: CCCCP(=O)(CC(O)(CN)c1ccc(Cl)cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCP(=O)([O-])CC(O)(CN)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1.2 g of ethyl 3-amino-2-(4-chlorophenyl)-2-hydroxy-propyl(n-butyl)phosphinate hydrochloride in 5 ml of ethanol is treated with 0.24 g of sodium hydroxide dissolved in 3 ml of water. The solution heated to 60° for 20 hours. After this time the solution is cooled to room temperature and washed 2-times with 50 ml each of dichloromethane and once with 50 ml of diethyl ether. The aqueous phase is evaporated to dryness. The residue is suspended in n-propanol, heated to 80° C. for 10 minutes and filtered. The n-propanol is removed in vacuo to afford a white solid. Chromatography on reverse-phase silica gel followed by drying in vacuo at 80° yields sodium 3-amino-2-(4-chlorophenyl)-2-hydroxy-propyl(n-butyl)phosphinate; m.p. 215°-215.5°; 1H-NMR spectrum (D2O): δ=7.4 ppm (4H, s), 2.91 ppm (2H, ABq), 2.22 ppm (2H, ABq,d), 1.37-1.0 ppm (6 H, m), 0.75 ppm (3H, t).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:34][C:35]([F:39])([F:38])[CH2:36][OH:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: OCC(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and 2,2,2-trifluoroethanol. White solid (98%). MS (EI): 582.1 (M−H)−.