Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl>C(O)C>[Cl:11][CH2:12][C:13]#[C:14][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCC#CCCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ClCC#CCOc1ccccc1
Temperature: 30 °C
Yield: 53.8 %

Procedure:
A mixture of phenol (50.8 g), potassium hydroxide (30 g), ethanol (200 ml) and water (50 ml) was stirred and heated under reflux for 1 hour, then cooled to 30° C. A solution of 1,4-dichlorobut-2-yne (100 g) in ethanol (60 ml) was added dropwise over 3.5 hours, then the mixture was stirred at ambient temperature for 18 hours and filtered. The filter cake was washed with ethanol (60 ml), and the filtrate and washings were combined. The solvents were removed in vacuo, and the residue was distilled to give 1-chloro-4-phenoxybut-2-yne as a colourless oil (52.5 g), b.p. 92°-98° C. at 0.53 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].[CH:10](O)(C)[CH3:11].ClCC=O>O>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: CC(C)O
Reactant: Nc1nnc(Cl)cc1Cl
Agent: O=CCCl
Solvent: O
Product: Clc1cc(Cl)c2nccn2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A mixture of 3-amino-4,6-dichloropyridazine (0.315 g, 1.92 mmol), 3 mL of isopropanol and 0.5 mL of a 50% chloroacetaldehyde in water solution was stirred at 80° C. for 20 h, then concentrated to remove isopropanol. The resulting yellow mixture was treated with 10 mL of a saturated aq. NaHCO3 solution and extracted with two 10 mL portions of dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (0->33% EtOAc/hexanes) afforded 0.313 g (87%) of 6,8-dichloro-imidazo[1,2-b]pyridazine as a light yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=O)[CH2:9][S:8][C:7]2[S:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:6]1=2)[CH2:2][CH2:3][CH3:4]>O1CCCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[S:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CSc2sc(C(=O)OC)cc21
Solvent: C1CCOC1
Product: CCCCN1CCSc2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
To a solution of 1-n-butyl-2,3-dihydro-6-methoxycarbonyl-2-oxo-1H-thieno[2,3-b][1,4]thiazine (31.9 g) in tetrahydrofuran (300 ml) was added dropwise boran-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (294 ml). After stirring for 3 hours at room temperature, the solvent was evaporated in vacuo and the residue was poured into water. The solution was adjusted to pH 8 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the object compound were collected and evaporated in vacuo to give 1-n-butyl-2,3-dihydro-6-methoxycarbonyl-1H-thieno-[2,3-b][1,4]thiazine (30.85 g).
Reaction SMILES: [O:1]([CH2:8][C:9](=O)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(CC(OCC)=O)C1C=CC=CC=1.C(OCC)(=O)C(OCC)=O.[NH2:37][C@H:38]([C:40]([N:42]1[CH2:49][CH2:48][CH2:47][C@H:43]1[C:44]([OH:46])=[O:45])=[O:41])[CH3:39].[OH-].[Na+].[BH3-]C#N.[Na+]>O>[C:10]([CH:9]([NH:37][C@H:38]([C:40]([N:42]1[CH2:49][CH2:48][CH2:47][C@H:43]1[C:44]([OH:46])=[O:45])=[O:41])[CH3:39])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:12])=[O:11]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)COc1ccccc1
Agent: CCOC(=O)COc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(=O)C(=O)OCC
Product: C[C@H](NC(COc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A slurry of phenoxypyruvic acid (1.8 g) (prepared by the condensation of ethyl phenoxyacetate with diethyl oxalate, followed by acid catalyzed hydrolysis and decarboxylation) and L-alanyl-L-proline (0.37 g) in 10 ml of water is adjusted to pH 7 with dilute NaOH. The mixture is treated with NaBH3CN (0.18 g) and allowed to stir at room temperature for 5 days. On the second and third days additional ketoacid (0.9 g) and sodium cyanoborohydride (0.18 g) are added. The product is adsorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water to yield, after freeze-drying, 0.5 g of N-(1-carboxy-2-phenoxyethyl)-L-alanyl-L-proline. The nmr is consistent with structure. The mass spectrum shows a peak at 479 for the silylated molecular ion minus methyl (494-15).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([C:14](Cl)=[O:15])[O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[NH3:27]>>[C:14]([C:12]1[O:13][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:9]=2[C:10](=[O:17])[CH:11]=1)(=[O:15])[NH2:27]
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Reactant: N
Product: CS(=O)(=O)Nc1cc2oc(C(N)=O)cc(=O)c2cc1Oc1ccccc1

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride was reacted with ammonia to obtain 2-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH3:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: Cc1cc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)ccc1F

Procedure:
The title compound, white solid (76 mg, 91%), MS (ISP) m/z=334.5 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: C1(COC([N:11]2[CH2:14][C:13]3([C@@H:18]([CH3:19])[NH:17][C:16](=[O:20])[O:15]3)[CH2:12]2)=O)C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][C@@H:18]1[C:13]2([CH2:14][NH:11][CH2:12]2)[O:15][C:16](=[O:20])[NH:17]1
Reactant: [H][H]
Reactant: C[C@H]1NC(=O)OC12CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: C[C@H]1NC(=O)OC12CNC2
Yield: 105.5 %

Procedure:
To a solution of (8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acid phenylmethyl ester (1.84 g, 6.6 mmol) in methanol (66 mL) was added wet 10% palladium on carbon (50% by mass, 500 mg). The resulting suspension was stirred under 1 atm of hydrogen for 1 h. The catalyst was then removed by filtration through celite. The filtrate was concentrated in vacuo to provide (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one as a white solid (0.99 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 5.23 (br s, 1H), 4.07 (d, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 3.79 (d, 1H), 3.58 (d, 1H), 1.38 (d, 3H); MS (EI) for C6H10N2O2: 143 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH:7]=1.[F:25][C:26]([F:42])([C:38]([F:41])([F:40])[F:39])[C:27]([C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)([F:29])[F:28]>[OH-].[Na+]>[CH3:19][C:16]1[C:15]([CH3:20])=[CH:14][C:13]2[O:12][C:8]3[C:9](=[CH:10][C:11]4[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:27]([F:29])([F:28])[C:26]([F:42])([F:25])[C:38]([F:41])([F:40])[F:39])[C:21]5[C:4]([O:5][C:6]=4[CH:7]=3)=[CH:3][C:2]([CH3:1])=[C:23]([CH3:24])[CH:22]=5)[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:27]([F:28])([F:29])[C:26]([F:42])([F:25])[C:38]([F:41])([F:40])[F:39])[C:18]=2[CH:17]=1
Reactant: O=C(c1ccccc1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(Oc2cccc(Oc3ccc(C)c(C)c3)c2)cc1C
Agent: *CC*
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(cc1C)C(c1ccccc1)(C(F)(F)C(F)(F)C(F)(F)F)c1cc3c(cc1O2)Oc1cc(C)c(C)cc1C3(c1ccccc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 140 °C
Yield: 75.1 %

Procedure:
A mixture of 159 g (0.5 mole) 1,3-bis(3,4-dimethylphenoxy)benzene, 274 g (1.0 mole) phenyl heptafluoropropyl ketone, and 280 g (14 moles) HF was heated in an autoclave for 8 hours at 140° C. After cooling, and venting off excess HF, the autoclave contents were transferred to a 1-gallon polyethylene jar, half filled with ice water, and containing 500 ml of 50% sodium hydroxide. The autoclave was rinsed out with methylene chloride, and the washings were added to the jar. The product was extracted with methylene chloride, the extracts were filtered through a layer of alumina, and the solvent was stripped off at atmospheric pressure yielding 312 g of a taffy-like residue, which was very soluble in acetone. The residue was extracted with several 500 ml portions of boiling methanol, and then was stirred with isopropyl alcohol, producing a solid in 21.3 g (5.1 % yield) with a sharp IR spectrum, devoid of OH bands, and melting in the 198-220° C. range, and after recrystallization from heptane at 237-238° C. NMR of the product melting over the wide range showed presence of cis- and trans- isomers: aromatic protons as multiplets 7.05-7.25, 6.85-7.0, broad s 6.66, two broad singlets at 6.58 and 6.50, and methyl singlets at 2.20 and 2.02 ppm in 6:7:2:1(total of the 6.58 and 6.50 peaks): 6:6 ratio. The recrystallized material was a single isomer, by NMR m 7.1, m 7.0, s 6.94, s 6.86, broad s 6.65, broad s 6.47, s 2.23 and s 2.04 ppm in 4:6:2:1:2:1:6:6 ratio. Analysis: calc. for C42H28F14O2 : C 60.7; H 3.37, F 32.0; F 32.0; found C 70.0; H 3.61, F 30.1%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1>>[F:30][C:24]1[CH:23]=[C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(Br)cc1F
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1F
Yield: 36.4 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (311 mg, 1.0 mmol) synthesized in Reference example 61 and 4-bromo-2-fluoroanisole (0.194 mL, 1.5 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 145 mg (yield 36%). Melting point was 161 to 163° C. (hexane).
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH:21]=O>O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 10.7 %

Procedure:
After a saturated hydrogen chloride-methanol solution 20 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-methoxy-4-ethoxybenzaldehyde 1.30 g, the mixture was srtirred for 18 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 100 ml of 55° C., and the mixture was stirred for 15 minutes and filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.216 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:31][C:28]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:26])[O:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:29][C:28]1([CH3:30])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:8][N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])=[CH:22][CH:21]=2)[O:31]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: [O-][n+]1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COn3ccccc3=O)cc2)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-hydroxypyridine-1-oxide (0.04 g, 0.34 mmol) was dissolved in 5 mL of anhydrous DMF. To this was added K2CO3 (0.14 g, 1.02 mmol) and 4-bromomethylphenyl boronic acid pinacol ester (0.10 g, 0.34 mmol). The reaction was heated to 80° C. and allowed to stir under nitrogen overnight. After cooling to room temperature, the solvent was evaporated and the resulting residue was brought up in dichloromethane and washed twice with water. The organic layer was dried over MgSO4, filtered and concentrated for purification via silica gel chromatography eluting with 2% MeOH in DCM. The protected B19 was collected as an off-white solid in 87% yield (98 mg, 0.3 mmol). 1H NMR (400 MHz, CDCl3) δ=7.79 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.24 (td, J=7.2 Hz, J2=2.0 Hz, 1H), 7.05 (dd, J=7.2 Hz, J2=2.0 Hz, 1H), 6.67 (dd, J=9.2 Hz, J2=1.2 Hz, 1H), 5.89 (td, J=6.8 Hz, J2=1.6 Hz, 1H), 5.29 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=159.2, 138.9, 137.0, 136.8, 135.3, 129.5, 122.9, 104.7, 84.3, 78.4, 25.1. ESI-MS(+): m/z 328.18 [M+H]+. Anal. calcd. for C18H22BNO4. 0.4 CH3OH: C, 65.26; H, 6.94; N, 4.16. Found: C, 65.54; H, 7.20; N, 3.76.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1>CC#N>[Br:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Solvent: CC#N
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)cn2)c1=O
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a suspension of 123a (231 mg, 0.96 mmol) in MeCN (40 mL) at 70° C. was added 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 101j (350 mg, 0.96 mmol). The reaction mixture was stirred for 3 days. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1) to afford 123b as yellow solid (452 mg, 90%). MS: [M+H]+ 524.7.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25]>ClCCl>[Cl:29][CH2:28][CH2:27][O:26][C:24]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:25]
Reactant: Cc1cccc(N)c1COc1cccn2c(C=O)c(C)nc12
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1COc1cccn2c(C=O)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine (2.36 g) and 2-chloroethyl chloroformate (1.3 g) in dichloromethane (150 ml) give the title compound as a brown oil which is used directly for further reaction in 3b.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][C:8]2([CH3:17])[CH3:16].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)C.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:18])=[CH:10][CH2:9][C:8]2([CH3:17])[CH3:16])=[CH:13][CH:14]=1
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC1=CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 403.8 %

Procedure:
Methyl magnesium bromide (3M solution in diethyl ether, 2.5 mL, 7.50 mmol) was added slowly to a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 35, 920 mg, 3.65 mmol) in 10 mL of diethyl ether at 0° C. After stirring and warming to room temperature for 2 h, the mixture was quenched with water at 0° C., extracted with diethyl ether (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure to give a light yellow oil. The crude oil was then dissolved in 10 mL of dichloromethane and stirred with 100 mg of para-toluenesulfonic acid at room temperature for 2 h. Water (10 mL) was then added and the organic layer was washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) gave the title compound (589 mg, 65% yield) as a colorless oil:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].[CH2:29](N(CC)CC)[CH3:30].C(Cl)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][C:29]([CH3:30])=[N:27][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: Cc1nnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To an ice cooled stirred mixture of 1.0 g (2.50 mmol) of the starting material XVIII, 35 ml of dichloromethane, 0.40 ml (2.75 mmol) of triethylamine and 0.22 ml (2.80 mmol) of acetyl chloride was added. The so obtained solution was left at room temperature for 16 h, then 0.6 g of p-toluenesulfonic acid was added and the mire was stirred at 40° C. for 2 h. Then the reaction mixture was washed with sodium hydrogen carbonate solution and water until neutrality, dried and concentrated. The crude product was treated with methanol, then recrystallized from ethanol to yield 0.99 g (91%) of the title compound. Mp.: 213-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[C:80]([C:84]1[CH:85]=[C:86]([NH2:91])[C:87]([NH2:90])=[CH:88][CH:89]=1)([CH3:83])([CH3:82])[CH3:81]>C(Cl)Cl>[NH2:91][C:86]1[CH:85]=[C:84]([C:80]([CH3:83])([CH3:81])[CH3:82])[CH:89]=[CH:88][C:87]=1[NH:90][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.1 g, 1.76 mmol), HATU (1 g, 2.64 mmol), HOAT (359 mg, 2.64 mmol) in DCM (30 mL) was added a solution of 4-tert-butylbenzene-1,2-diamine (433 mg, 2.64 mmol) and TEA (533 mg, 5.28 mmol) in DCM (10 mL) dropwise, then the resultant reaction mixture was stirred at rt overnight. After diluted with DCM (50 mL), the mixture was washed water (30 mL×3), dried and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 40:1) to afford the desired compound (680 mg, yield: 50%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.16 (s, 1H), 7.19 (d, J=3.5 Hz, 1H), 7.14-7.10 (m, 1.7H),6.99-6.97 (m, 0.6H), 6.92 (s, 0.6H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 6.66-6.65 (m, 1H), 6.54-6.53 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.36-5.35 (m, 1H), 4.96-4.95 (m, 1H), 4.65 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.17-2.73 (m, 4H), 2.33-1.71 (m, 8H), 1.58 (s, 3H), 1.53-1.50 (m, 1H), 1.38 (s, 3H), 1.28 (s, 9H), 1.0 (d, J=5.5 Hz, 3H), 0.84 (d, J=5.0 Hz, 3H) ppm; LC-MS (m/z): 770.0 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:19]4[C:18]([C:4]=2[CH:3]=1)=[CH:17][CH:16]=[CH:15][C:14]=4[C:13]([CH3:21])([CH3:20])[C:12]1[C:7]3=[CH:8][CH:9]=[N:10][CH:11]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:20][C:13]1([CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[N:6]2[C:19]3[C:18]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:23]=[CH:22][C:5]=42)=[CH:17][CH:16]=[CH:15][C:14]1=3
Reactant: COB(OC)OC
Reactant: CC1(C)c2cnccc2-n2c3ccc(Br)cc3c3cccc1c32
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
94 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification. Yield: 59 g (181 mmol), 70% of theory, purity according to 1H-NMR about 96%.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O([CH2:39][C:40]([F:43])([F:42])[F:41])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:24]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[C:15](=[O:16])[N:14]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C@@H:10]1[CH2:22][CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Yield: 56.4 %

Procedure:
A solution of 0.50 g (1.24 mmol) (−)-(6R,7S)-7-dibenzylamino-6-ethyl-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one and 0.44 g (1.85 mmol) 2,2,2-trifluoroethyl triflate in 5 ml dimethylformamide were treated with 0.61 g (1.85 mmol) cesium carbonate for 18 hours. The mixture was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 70:30 yielded 0.34 g (57%) (6R,7S)-7-dibenzylamino-6-ethyl-2-fluoro-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 487.4 (M+H+, 100).