Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[C:11](OC)([O:14]C)[C:12](=[O:13])[CH:6]1[CH:7]=[C:8]2[Br:18])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[C:11](=[O:14])[C:12](=[O:13])[CH:6]1[CH:7]=[C:8]2[Br:18])=[O:4]
Reactant: COC(=O)C1CC2C(Br)=CC1C(=O)C2(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C1CC2C(=O)C(=O)C1C=C2Br

Procedure:
3 g (9.4 mmol) of 5-bromo-8,8-dimethoxy-7-oxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester (J.O.C. (202), 67, 6493) are stirred in a mixture of 15 ml of trifluoroacetic acid and 1 ml of water for 12 hours at room temperature. Extraction is then carried out with dichloromethane against water. The organic phase is dried over sodium sulfate and yields, after removal of the solvent, the 5-bromo-7,8-dioxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester in the form of an orange-coloured oil and as a pure isomer.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:25][C@@H:26]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CCOC(C)=O>[OH:25][C@@H:26]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:42]=1)[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCO2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCO2)c1

Procedure:
tert-Butyl ((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)-carbamate was prepared by the reaction between rac-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) at +100° C. following the method used in Example 12 with the following exception. After the reaction was complete (as judged by TLC), the reaction mixture was diluted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave the product as an off-white semi-solid. Yield (0.36 g, 66%); 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, 1H), 4.88 (bs, 1H), 4.71 (bs, 1H), 4.28-4.25 (m, 1H), 3.96-3.90 (m, 3H), 3.85-3.82 (m, 1H), 3.49 (bs, 1H), 3.19-3.13 (m, 2H), 1.97-1.92 (m, 2H), 1.83-1.74 (m, 3H), 1.60 (s, 1H), 1.45 (s, 9H); MS: m/z 352.8 [M+H]+.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[H-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1cc(O)nc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(=O)[nH]c(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7.1 g) was added portion wise to a stirred suspension of 60% sodium hydride (2.4 g) in dry N,N-dimethylformamide (70 ml). After 1 hour a solution of 2,3-Difluorobenzyl bromide (10 g) in dry N,N-dimethylformamide (10 ml) was added. Stirred over weekend at room temperature. Poured on to ice/water and the precipitate was collected by filtration to give 9.6 g of product. 81% yield.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
After a mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (650 mg), 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature for three hours, 1 N hydrochloric acid (5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (560 mg, yield: 91%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 197–198° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[OH:23])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-benzo[1,3 ]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as white crystals after crystallization from hexane; m.p.: 128-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14][CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH2:16][CH2:15][CH:14]=[CH2:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1c(F)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde from step 4A (2.0 g, 9.13 mmol) in DMF (36.5 ml) was added 4-bromo-1-butene (3.71 ml, 36.5 mmol) and potassium carbonate (1.58 g, 11.4 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, and then filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-20% EtOAc/hexanes) gave 5-bromo-2-(but-3-enyloxy)-3-fluorobenzaldehyde (2.38 g, 8.71 mmol, 95% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.22 (d, J=0.9 Hz, 1H), 7.98 (dd, J=11.3, 2.4 Hz, 1H), 7.63 (dd, J=2.4, 1.2 Hz, 1H), 5.89 (ddt, J=17.1, 10.4, 6.7 Hz, 1H), 5.17 (dd, J=17.2, 1.7 Hz, 1H), 5.12-5.07 (m, 1H), 4.29 (t, J=6.4 Hz, 1H), 2.57-2.49 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=S)[NH:11][NH2:12])=[C:4]([CH3:14])[CH:3]=1.Cl[CH:16]([C:22]([CH3:24])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([CH3:24])[NH:12][N:11]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(C)cc(Br)cc2C)n[nH]c1C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A mixture of 14.6 g (0.06 mole) of 4-(4-bromo-2,6-dimethylphenyl)-3-thiosemicarbazide and 9.93 g (0.06 mole) of ethyl 2-chloroacetoacetate in 60 mL of absolute ethanol was stirred under nitrogen atmosphere for 2 hr, treated with 30 mL of 2N ethanolic hydrogen chloride and heated at reflux until the reaction mixture cleared (3 hr). The reaction mixture was filtered hot then concentrated in vacuo to give an orange solid which, when triturated with warm benzene/ligroin (50:50) and filtered gave 10.8 g of slightly orange crystalline product. The filtrate upon standing for ~16 hr gave an additional 4.4 g of yellow crystals which became white when washed with warm acetone. The 2 fractions were combined and recrystallized from benzene/ligroin to give 10.35 g of fine white crystalline rods, mp 171°-199° C. (with degassing). An NMR analysis showed the solid to be a salt with some solvent present; mass spectra confirmed the presence of hydrogen chloride. After drying at 82° C. under high vacuum, there was left 9.56 g, mp 168°-196° C. A broad melting point range suggested that it may be a mixture of free base and salt; therefore, it was dissolved in methanol/water along with other reaction mixture material, made basic with 3N sodium hydroxide and extracted with 5×60 mL of methylene chloride. The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a dark yellow solid. Recrystallization from benzene/ligroin then from benzene gave 10.7 g of white granular powder, mp 184°-185° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[F:46][C:47]1[CH:48]=[C:49]([NH2:55])[CH:50]=[N:51][C:52]=1[O:53][CH3:54].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[F:46][C:47]1[CH:48]=[C:49]([NH:55][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[CH3:35])=[CH:4][N:3]=2)[CH:50]=[N:51][C:52]=1[O:53][CH3:54]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (752 mg, 1.20 mmol) and 5-fluoro-6-methoxypyridin-3-amine (175.0 mg, 1.231 mmol) were dissolved in THF (12.0 mL) and the flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethylbenzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred under nitrogen. After 15 min, the reaction was treated with ice water (1.5 mL) and diluted with DCM (150 mL). The solution was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (744.3 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (s, 1H), 8.66 (d, J=2.35 Hz, 1H), 8.17 (d, J=2.54 Hz, 1H), 8.03 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.81 (d, J=8.41 Hz, 2H), 7.40 (d, J=8.41 Hz, 2H), 7.24-7.14 (m, 4H), 7.90-7.81 (m, 4H), 4.87 (d, J=5.09 Hz, 2H), 4.77 (d, J=5.48 Hz, 2H), 4.21 (q, J=7.04 Hz, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.98 (s, 3H), 2.58 (s, 3H), 1.67 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 750 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26](Cl)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Temperature: 90 °C
Yield: 149.9 %

Procedure:
5 g phenylboronic acid in 30 mL dioxane was added to 3.2 g 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester and 388 mg (1,1′-bis(diphenyl-phosphinoferrocene)palladium(II)dichloride in 50 mL dioxane under argon. The reaction was stirred at 90° C. over night. The mixture was cooled to RT diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide and brine. The solvent was removed and the precipitate was purified by column chromatographie to yield 5.5 g of the desired product. (M+H)+=325
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[O:27][C:23]=5[CH:22]=4)[CH2:17][CH2:16]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][N:14]([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@H:18]([C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[O:27][C:23]=5[CH:22]=4)[CH2:19][CH2:20]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCC4CC(c5ccc(F)cc5)=NO4)CC3)cc2o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC1CC(c2ccc(F)cc2)=NO1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
A mixture of trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-amino}-cyclohexyl)-3H-benzoxazol-2-one (51) (190 mg, 0.464 mmol) from Step 7, p-formaldehyde (70 mg, 2.32 mmol), and 2N NaOH (1 mL) in MeOH (15 mL) was stirred for 3 hours, NaBH(OAc)3 (138 mg, 0.650 mmol) was added, and the reaction mixture was stirred overnight. Solid NaOH was added until the solution turned clear. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, 95:5:1 CH2Cl2:MeOH:NH4OH) gave trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-methyl-amino}-cyclohexyl)-3H-benzoxazol-2-one (52) (60 mg, 31%), as a white foam: mp 109-114° C.; IR (KBr): 3430, 2927, 1772 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 7.74 (dd, J=6, 3 Hz, 2H), 7.27 (m, 2H), 7.13 (s, 1H), 6.97 (m, 2H), 4.55 (m, 1H), 3.33 (m, 2H), 3.18 (m, 2H), 2.56 (m, 1H), 2.44 (m, 1H), 2.28 (s, 3H), 1.87 (m, 4H), 1.38 (m, 2H), 1.26 (m, 2H); API-MS (m/z): 424 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C24H26FN3O3, 424.2036; found, 424.2036; HPLC: method A, 5.39 minutes (98.1%); method B, 10.86 minutes (>99%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C([O-])([O-])=[O:16].[Ca+2]>O1CCOCC1.O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH2:2][OH:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Br)c(CO)c(Br)c1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (12.53 g, 32.4 mmol, 1 eq) in dioxane (100 mL) and water (100 mL) was added CaCO3 (8.1 g, 81 mmol, 2.5 eq). The mixture was warned to and stirred at 100° C. until reaction was complete by HPLC analysis. The mixture was cooled and the solvent removed under reduced pressure. The residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated giving methyl 3,5-dibromo-4-(hydroxymethyl)benzoate. The material was taken immediately to the next step.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25]CC)=[O:24])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:28])[CH:16]=3)[N:11](C(OC(C)(C)C)=O)[C:10]=2[C:9]1=[O:36])=O)(C)(C)C.[Li+].[OH-]>CO.O>[F:28][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:36])[NH:8][CH2:21][CH:20]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[C:18]2=1
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C(=O)c2c1c1cc(F)ccc1n2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-ethoxycarbonylmethylene-7-fluoro-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylic acid di-tert-butyl ester, (1.31 g, 2.6 mmol) in MeOH—H2O (3:1 mixture, 150 mL) is added LiOH (0.312 g, 13 mmol). The mixture is stirred at room temperature for 2 days and concentrated. Water (100 mL) is added to the residue and it is acidified with 2M NaHSO4. The precipitate is collected by filtration and dried to give (7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; 1H NMR (DMSO-d6) δ 2.26 (d, 2H, J=5.2 Hz), 2.79 (s, 2H), 5.00 (t, 1H, 6.4 Hz), 6.22 (dt, 1H, J1=2.4 Hz, J2=10.8 Hz), 6.56 (dd, 1H, J1=4.0 Hz, J2=8.8 Hz), 6.66 (dd, 1H, J1=2.4 Hz, J2=10.8 Hz), 7.26 (t, 1H, J=5.6 Hz), 11.10 (s, 1H); m/z [M++1] 275.0.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: CNc1nnc(C(C)(C)C)s1

Procedure:
feeding the contents of said first and second vessels concomitantly into a third vessel containing a heel, i.e., a reacted mixture having been formed previously by reacting 4-methyl-3-thiosemicarbazide with a solution of pivalic acid in the presence of a solution containing concentrated polyphosphoric acid and concentrated sulfuric acid to form 5-t-butyl-2-methylamino-1,3,4-thiadiazole in situ;
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]4[CH2:20][O:21][C:22]5[CH:53]=[C:52]6[C:25]([CH:26]=[CH:27][C:28]7[N:32]=[C:31]([C@@H:33]8[CH2:37][CH2:36][CH2:35][N:34]8[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]8[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=8)[NH:30][C:29]=76)=[CH:24][C:23]=5[C:17]4=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61])=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:49][O:48][C:47]([NH:46][C@H:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:38]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]1[NH:30][C:29]2[C:52]3[C:25]([CH:26]=[CH:27][C:28]=2[N:32]=1)=[CH:24][C:23]1[C:17]2[C:18]([CH2:20][O:21][C:22]=1[CH:53]=3)=[CH:19][C:14]([C:11]1[NH:10][C:9]([C@@H:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH:63]([CH3:65])[CH3:64])=[N:13][CH:12]=1)=[CH:15][CH:16]=2)=[O:51])=[O:50]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (55 mg, 0.077 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14 mg, 0.077 mmol), HATU (32 mg, 0.085 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (30.7 mg)
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[C:23]([CH2:33][CH3:34])=[N:24][N:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1>O.CCO.Cl>[CH2:33]([C:23]1[C:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)=[C:26]2[N:27]=[C:28]([CH3:32])[CH:29]=[C:30]([CH3:31])[N:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzhydrylidene-[4-(2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-amine (12) (3.97 g, 8.93 mmol) was dissolved in a mixture of water (40 ml), EtOH (10 ml) and conc. HCl (10 ml) and stirred at rt for 1 h. The reaction mixture was basified to pH 11 with Na2 CO3. The organic layer was extracted with EtOAc, washed with water and brine, dried over Na2 SO4 and concentrated to afford an orange oil. The crude product was purified by chromatography (2-50% EtOAc in cyclohexane) to afford a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([OH:14])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[H-].[Na+].I[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([O:14][CH:19]([CH3:21])[CH3:20])=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)I
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(C(C)(C)C)c(OC(C)C)c1C=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140, 0.58 g, 2.14 mmol) in anhydrous N,N-dimethylformamide (10 mL) was treated with sodium hydride (0.34 g of 60% suspension in mineral oil, 8.56 mmol). After 30 minutes, 2-iodopropane (1.3 mL, 12.84 mmol) was added and the reaction mixture was heated at 75° C. overnight. The reaction mixture was then cooled and poured into iced water and extracted with diethyl ether. The organic extract was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 2-4% ethyl acetate in hexane as the eluent afforded the title product (0.43 g, 64%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-trifluoromethylbenzyl chloride (4{15}, 5 g, 25.7 mmol, 1 equiv.), piperazine (13.3 g, 154.2 mmol, 6 equiv.), THF (56.1 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{15} (3.97 g, 67%) as a light yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.52 (d, 2H, J=8.0 Hz), 7.40 (d, 2H, J=8.0 Hz), 3.48 (s, 2H), 2.84 (t, 4H, J=4.8 Hz), 2.36 (br s, 4H), 1.55 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 142.4, 129.1 (q, JC-F=32.1 Jz) 129.1 (br), 125.0 (br), 124.1 (q, JC-F=338.0 Hz), 62.9, 54.4, 45.9. 19F-NMR (375 MHz, CDCl3): δ-62.5.