Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([OH:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:3]([OH:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCC(O)(c1ccc(F)cc1)c1ccc(OCCBr)cc1
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCCN2CCCCC2)cc1
Reaction time: 2 h

Procedure:
17.6 g. of α-ethyl-α-(4-fluorophenyl)-4-(2-bromoethoxy)-benzylalcohol and 30 ml. of dry piperidine are refluxed with stirring for two hours. Piperidine is distilled off from the reaction mixture under reduced pressure, to the residue water is added, and it is extracted with ether. The ethereal phase is washed to neutral with water, dried over anhydrous potassium carbonate, and then ether is distilled off. Crystallization of the residue from n-hexane yields 14.9 g. of the named compound, melting at 72° to 73° C.
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.C(OCC)C.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:19][C:16]1([CH3:18])[C:17]2[C:12]([CH:11]=[C:10]3[C:9]=2[CH:8]=[N:7][N:6]3[CH2:5][C@@H:4]([NH2:1])[CH3:21])=[C:13]([CH3:20])[CH:14]=[CH:15]1
Reactant: CC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Product: CC1=C2C=c3c(cnn3C[C@H](C)N)=C2C(C)(C)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
0.7 g (2.5 mmol) of (S)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous methanol was hydrogenated over 70 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 290 mg (2.5 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 4 hours and the white crystals were subsequently filtered off. 0.5 g (54%) of (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 158° was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Intermediate B (74.0 mg, 454 μmol) was added to a mixture of NaH (60% in mineral oil, 27.2 mg, 681 μmol) in DMF (2.5 mL) at RT and stirred for 15 min. Intermediate 3b (100 mg, 454 μmol) was then added and the resulting mixture heated to 60° C. for 1 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The resulting residue was purified by FCC, using 0 to 10% [2M NH3 in MeOH] in DCM, to afford the title compound as an orange residue (122 mg, 74%). LCMS (Method 3): Rt 2.13 min, m/z 364 [MH+].
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:18])=[N+]=[N-]>CO.O.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:18]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a mixture of 5′-azido-2′,5′-dideoxyuridine (5 g, 0.0197 mol) in methanol/water (150 mL, 1:1) was added Pd/C (0.25 g, 10%) under N2 atmosphere and then hydrogenated for 4 h at RT. The reaction mixture was filtered through bed of celite and the filtrate was concentrated under vacuum. The solid obtained was washed with 3% methanol in chloroform which gave the title product (4.1 g, 89%) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[C:10]2[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:10]1[C:9]2[C:14](=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH:6]=[CH:7][CH:8]=2)[N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCN)c2n1
Product: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCNS(C)(=O)=O)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(2,4-dichlorobenzyl)-amine (example 36) and methanesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12]Br.[F-].[K+].[F-].[Cs+]>CN(C)C=O>[CH:7]1[C:4]([CH:5]=[O:6])=[CH:3][C:2]2[O:1][CH2:12][O:10][C:9]=2[CH:8]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCBr
Agent: [Cs+]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCO2
Yield: 90 %

Procedure:
One process for preparing piperonal from 3,4-dihydroxybenzaldehyde comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride and alkali in a non-protic polar solvent such as dimethyl sulfoxide, and gives a 61% yield of piperonal (British Pat. No. 1,097,270). Another process comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride in aqueous alkali under the influence of an interphasic moving catalyst such as quaternary ammonium compound, and gives a 70-73% yield of piperonal. However, the catalyst used in this process is expensive and, by nature, easily soluble in both aqueous and organic phases. Accordingly, the recovery of the catalyst is too low to make this process practicable (Japanese Patent Application Disclosure Nos. 23,265/'76 and 113,967/'77). In any event, neither of these process can provide satisfactory yields based on the amount of the starting material. In addition, James H. Clark et al. have described still another process in which 3,4-dihydroxybenzaldehyde is reacted with dibromomethane in N,N-dimethylformamide under the influence of an excess of potassium fluoride or cesium fluoride to give a 90% yield of piperonal [Tetrahedron Letters, No. 38, pp. 3361-3364 (1976)]. This process is of advantage in that no strong base is used, the reaction time is relatively short, and a high yield can be obtained. However, an expensive fluoride must be used in large excess as a halogen trapping agent and cannot be recycled because its fluorine component is stoichiometrically replaced by the halogen atoms in the dihalomethane used. Accordingly, this process is not satisfactory for industrial applications. Moreover, when based on the amount of pyrocatechol used, the yield attainable with this process does not reach 70%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=CC=[CH:5][C:4]=1C)[CH3:2].[C:10]1(=[O:20])[O:15][C:13](=O)[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C1(C)C=CC=CC=1>[C:3]1([CH3:8])[CH:4]=[CH:5][C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([OH:15])=[O:20])=[CH:2][CH:1]=1
Reactant: CCc1ccccc1C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 70 °C
Yield: 107.5 %

Procedure:
To a mixture of 108 g of the complex obtained in Example 1 and 92 g of toluene were added gradually 14.8 g of phthalic anhydride while stirring, and the mixture was maintained at 70°C for 2 hours after the addition. The reaction mixture was treated as usual to obtain 22.8 g of o-(p-toluyl)-benzoic acid.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]2[C:82]3[C:81]([F:84])([F:83])[CH2:80][CH2:79][C:78]([F:86])([F:85])[C:77]=3[C:76]([CH:87]([F:89])[F:88])=[N:75]2)[CH2:62][C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=2)=[N:52][C:53]([NH:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)=[N:54][CH:55]=1>>[CH:58]1([CH2:57][NH:56][C:53]2[N:52]=[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]3[C:82]4[C:81]([F:83])([F:84])[CH2:80][CH2:79][C:78]([F:85])([F:86])[C:77]=4[C:76]([CH:87]([F:89])[F:88])=[N:75]3)[CH2:62][C:63]3[CH:64]=[C:65]([F:70])[CH:66]=[C:67]([F:69])[CH:68]=3)[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=2)[CH2:59][CH2:60]1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCC2CC2)ncc1Br
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: NC(=O)c1cc(-c2cnc(NCC3CC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (13B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 13A. 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=7.7 Hz, 1H), 7.73 (s, 1H), 7.24-7.02 (m, 2H), 6.90 (dd, J=10.7, 8.6 Hz, 1H), 6.65-6.24 (m, 2H), 6.13 (d, J=6.1 Hz, 2H), 4.91 (m, 1H), 4.83-4.62 (m, 2H), 3.09 (m, 2H), 2.71 (ddd, J=20.2, 13.3, 7.4 Hz, 2H), 2.37-2.06 (m, 4H), 0.88 (m, 1H), 0.47-0.16 (m, 2H), 0.02 (q, J=5.1 Hz, 2H). MS (m/z) 726.30 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([Br:20])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].CCOCC>O1CCOCC1>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[Br:20][C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)c(OCc3cccc(Cl)c3)n2)CC1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Clc1cccc(COc2nc(N3CCNCC3)cnc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.2 %

Procedure:
A solution of 5′-bromo-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3j (25 mg, 0.052 mmol) in 1,4-dioxane (0.5 ml) was treated with methanesulfonic acid (6.7 μl, 0.104 mmol) was stirred at room temperature for 16 h. The mixture was treated with ether to afford a precipitate. The supernatant was removed. The residue was treated with ether. The supernatant was again removed to provide a solid (26 mg, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:20])[CH2:11][C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1.[H][H]>C(O)C.CO.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: OC(CC#Cc1cccnc1)CC#Cc1cccnc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Solvent: CCO
Product: OC(CCCc1cccnc1)CCCc1cccnc1
Yield: 98.9 %

Procedure:
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi of hydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:10]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
2-Hydroxybenzaldehyde (5.14 g, 42.1 mmol) was added to a suspension of tert-butyl-dimethyl-silyl chloride (6.7 g, 44.4 mmol) and imidazole (3.03 g, 44.5 mmol) in dichloromethane (100 ml) under an atmosphere of nitrogen at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and then washed sequentially with 1 M hydrochloric acid (2-fold 50 ml) followed by a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residual yellow oil was passed through a plug of silica gel eluting with 1:1, by volume, dichloromethane:pentane giving 2-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (8.6 g) as a golden yellow oil.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[BrH:12].N([O-])=O.[Na+]>O.O1CCOCC1>[Br:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Br
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(O)c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at 0° C., the mixture transferred to a jacketed dropping funnel (0° C.) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48%; 16.7 mL; 147 mmol) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., stirred for an additional 15 min., cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; CH2Cl2 as the solvent) to afford pure 2-bromo-3-nitrophenol 1b2 (45%; 3.16 g) as an orange-brown solid. MS 217.8 (MH)−. Homogeneity by HPLC (TFA)@220 nm: 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([Cl:14])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:11])(=[O:12])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=S1(=O)C=Cc2cc(Br)ccc2O1
Product: O=S1(=O)C=Cc2cc(Br)cc(S(=O)(=O)Cl)c2O1
Temperature: 0 °C

Procedure:
6.0 g of 6-bromo-2,2-dioxo-1,2-benzoxathiine and 22.0 g of chlorosulfonic acid are heated for 1 hour to 60° C. The mixture is then poured into ice-water. The precipitated 6-bromo-8-chlorosulfonyl-2,2-dioxo-1,2-benzoxathiine is isolated, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][C:5]2[N:6]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18]C(=O)C)[C@H:12]3[O:13]C(=O)C)[C:7]([C:9]#[CH:10])=[N:8][C:4]=2[CH:3]=1>ClCCl>[Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][C:5]2[N:6]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([OH:18])[C@H:12]3[OH:13])[C:7]([CH:9]=[CH2:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C#Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClCCl
Product: C=Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O

Procedure:
5,6-Dichloro-2-ethynyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl) 1H-benzimidazole (0.85 g, 0.20 mmol) was deprotected using general procedure III. Crude product was purified by silica gel chromatography using 1:10 methanol:dichloromethane to give the title compound as an off white solid (0.04 g, 0.12 mmol, 59%); MS (ES+): m/z (rel. intensity) 351 (15, M++Na);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and phenylboronic acid (122 mg, 1.0 mmol) to afford after chromatographic purification the title compound (74 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>O1CCCC1>[Cl:14][C:2]1([Cl:1])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=[O:13]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (1.0 g, 4.32 mmol) and ethyl bromoacetate (0.51 ml) in of tetrahydrofuran (30 ml) was added dropwise with stirring during 15 minutes to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 ml) at room temperature under a nitrogen atmosphere. Stirring was continued for an additional 2 hours. The solution was quenched by addition of saturated aqueous ammonium chloride and the solvents were removed under reduced pressure. The residue was extracted with ether (3×20 ml), and the combined ether solutions washed with saturated brine (20 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. NMR(CDCl3): δ1.27 (t, 3H); 3.22 (m, 4H); 4.25 (q, 2H); 4.65 (s, 2H), 7.3 (m, 4H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:10](=O)[CH2:11][C:12](OCC)=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=[CH:11][C:12]1=[O:13]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=c1ccc2ccccc2o1

Procedure:
Scheme VIII describes the synthesis of 6-alkylaminocoumarins, as demonstrated by Structure 45, from phenol through a similar route as that described in Schemes I and II. A mixture of a phenol compound and a 3-ketoester such as ethyl 4,4,4-trifluoroacetoacetate are heated in refluxing toluene in the presence of TsOH to afford a coumarin compound e.g., Structure 43. Nitration of coumarin compounds (e.g., Structure 43) followed by hydrogenation give aminocoumarin compounds such as Structure 44. Sequential reductive alkylation provides dialkylamino-coumarin compounds as shown in Structure 45. Hydrogenation of a dialkylamino-coumarin compound (e.g., Structure 45) affords compounds Structure 46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20]O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.ClCCl.P(Br)(Br)[Br:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][Br:27])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1nc2n(c1CO)C1CC(C1)c1ccc(Br)cc1-2
Solvent: ClCCl
Product: COC(=O)c1nc2n(c1CBr)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate in dichloromethane (1 eq) was added phosphorus tribromide. After 20 minutes of stirring at room temperature, the reaction was extracted with a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford crude methyl 10-bromo-3-(bromomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxy late. To this intermediate in a solution of N,N-dimethylformamide (5 mL/mmol) was added 2-chlorophenol (2 eq) and cesium carbonate (1.5 eq). The reaction was stirred at 50° C. and monitored by LC-MS until complete, whereupon the reaction mixture was extracted with dichloromethane and a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford 147 mg (59%) crude methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 124 mg (91%) of 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide, 50 mg of which was directly reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 31 mg (55.4%) of 3-[(2-chlorophenoxy)methyl]-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8]([C:5]3[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=3)=[O:10])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: Cc1cc(C(=O)O)ncc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C(=O)c3cc(C)c(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a mixture of 5-bromo-4-methylpyridine-2-carboxylic acid (0.400 g, 1.85 mmol, 1.0 eq) and 4-(4-methoxybenzoyl)piperidine hydrochloride (0.474 g, 1.85 mmol, 1.0 eq) was added dimethylformamide (10 mL) followed by triethylamine (0.64 mL, 4.36 mmol, 2.5 eq). HATU (0.774 g, 2.04 mmol, 1.1 eq) was added forming a yellow solution, which was stirred at room temperature for 1 day. The reaction was partitioned between EtOAc (120 mL) and water-NaHCO3 (1:1, 120 mL). The organics were further washed with brine (120 mL), water (120 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the title compound (0.693 g, 89%) as a yellow oil; 1H nmr (CDCl3) δ 8.55 (1H, s, pyH-3 or H-6), 7.90 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.48 (1H, s, pyH-3 or H-6), 6.91 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.64 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.83 (3H, s, OCH3), 3.49 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.03 (1H, m, 1H of BzpipH-2, H-6), 2.39 (3H, s, pyCH3), 1.95 (1H, m, 1H of BzpipH-3, H-5), 1.86-1.75 (3H, s, 3H of BzpipH-3, H-5); m/z 417, 419 [M+H]+.