Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH2:14]1.[CH3:22][C:23](O)([CH3:25])[CH3:24]>C(Cl)Cl>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:20])[CH2:14]1
Reactant: CC(C)(C)O
Reactant: O=C1CCCC(C(=O)O)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous MgSO4 (3.4 g, 28 mmol) was suspended in DCM (28.1 mL) and to this vigorously stirred mixture was added concentrated sulfuric acid (0.7 g, 7 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. 3-Oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) was added followed by t-BuOH (2.6 g, 35 mmol). The resulting mixture was allowed to stir for 24 hours before it was filtered and flushed with DCM. The filtrate was washed with water, and the organic layer was again washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound. The residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8].O.Cl>CCOCC.C(N(CC)CC)C>[Cl:9][C:3]1([F:8])[C:2]([Cl:1])=[CH:5][C:4]1([F:7])[F:6]
Reactant: FC1(F)CC(Cl)(Cl)C1(F)Cl
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: FC1(F)C=C(Cl)C1(F)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1,1,2 trichloro-2,3,3-trifluorocyclobutane (55.5 g) in 100 ml of anhydrous ether, triethylamine (40 ml) was added dropwise over 30 min at room temperature, and the mixture was stirred overnight at ambient temperature. The mixture was then stirred with 120 ml H2O and 7.5 ml of concentrated HCl. The ether layer was washed with H2O (100 ml), brine (100 ml), dried over anhydrous MgSO4, and evaporated in vacuo. The residue was distilled fractionally at atmospheric pressure from 64°-68° C. to yield 36 g (79%) of a colorless liquid as pure product.
Reaction SMILES: Br[C:2]1C=CC(Cl)=C(C(C2C=CC(OCC)=CC=2)O)C=1.[H-].[Na+].CI.Cl.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([CH:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)[O:33][CH3:34])[CH:31]=1>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:44])=[C:30]([C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)([O:33][CH3:34])[CH3:2])[CH:31]=1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Reactant: CCOc1ccc(C(OC)c2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(C(C)(OC)c2cc(Br)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
3.42 g of (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)methanol prepared according to example 1 and 10 ml of anhydrous THF were added into a 100-ml round-bottomed flask, and the resulting solution was cooled in ice-water bath and magnetically stirred. 0.40 g (60%) of solid NaH was added in portions, after which, the resulting mixture was stirred for another one hour, and then 1.70 g of dried MeI was added. The reaction mixture was stirred overnight at room temperature, poured carefully into 200 ml of ice water, and adjusted pH to 4-5 with concentrated hydrochloric acid. The resulting acidic mixture was extracted twice with 100 ml of dichloromethane. The combined extracts were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to afford a colorless oily product, which was (5-bromo-2-chlorophenyl)(4-ethyoxyphenyl)(methoxy)methane. ESI-MS, m/z=355.2 ([M(79Br)+1]), 357.2 ([M(81Br)+1]).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[CH:11]=[C:10]([C:12](O)=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]>CN(C=O)C.C(Cl)Cl>[CH2:5]([N:7]1[CH:11]=[C:10]([C:12]([Cl:3])=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(=O)Cl)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of thionyl chloride (2.0 mL) and 2 drops of DMF in DCM stirring under nitrogen at RT is added the title compound of Example 3, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid (0.8 g, 1.65 mmol) in one portion. The resulting suspension is stirred for 16 h. The solution is concentrated and the resulting residue is azeotrophed twice with toluene. It is used as such without any additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:16]([C:18]2[N:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:17])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](OC)=[O:31])[CH:25]=1.C(O)C.[BH4-].[Na+]>O.CC(C)=O>[F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=2)=[CH:4][C:5]([CH2:8][N:9]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:16]([C:18]2[N:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2cc(CN(C(=O)c3ncn(C)n3)C3CCOCC3)ccc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(-c3cccc(CO)c3)c2)C2CCOCC2)n1
Yield: 5.7 %

Procedure:
A mixture of methyl 2′-fluoro-5′-([[(1-methyl-1H-1,2,4-triazol-3-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino]methyl)biphenyl-3-carboxylate (318 mg), ethanol (14 mL) and sodium borohydride (532 mg) was heated under reflux for 16 hours. After leaving the mixture to cool, water-acetone was added and extraction was conducted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; methanol/chloroform=1:99 to 3:97) to give the titled compound (17 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH3-])(=O)C.[Na+].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN1CCNCC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice-cooling, 29.2 g (256 mmol) of N-ethylpiperazine and 50.0 g (256 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to 1-Boc-4-piperidone) were initially charged in 800 ml of ethanol and 15.4 g (256 mmol) of glacial acetic acid were added. A little at a time, 16.1 g (256 mmol) of sodium acetoxyborohydride was then added to the cooled reaction mixture. Initially, a slight evolution of gas and, after ⅔ of the reducing agent had been added, foaming could be observed. The reaction mixture was stirred at room temperature overnight. For work-up, 200 ml of 2 N aqueous sodium hydroxide solution were added with cooling to the reaction solution, the solvent ethanol was distilled off and the reaction mixture which remained was diluted with water. The mixture was extracted with diethyl ether (2×) and washed with saturated sodium chloride solution (1×), the combined organic phases were dried over magnesium sulphate and filtered and the solvent was removed under reduced pressure. The desired product was obtained as a yellow oil which was subsequently chromatographed on a 4 l Nutsche filter filled with silica gel, using dichloromethane and 10% methanol as eluents. This gave a total of 40 g (135 mmol, 53%) of tert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:45][C:46]1([F:50])[CH2:49][NH:48][CH2:47]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:48]4[CH2:49][C:46]([F:50])([F:45])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 80 mg, 0.126 mmol) in 1 mL THF was added to 1 dram vial that contained 3,3-difluoroazetidine hydrochloride (11.8 mg, 0.126 mmol). Triethylamine (0.071 mL, 0.506 mmol) was added, the vial was capped and the reaction mixture heated to 60° C. for 3 hours. The mixture was cooled to ambient temperature and stirred overnight. Diluted the mixture with ethyl acetate (2 mL) and washed with H2O (3×1 mL), brine (1×1 mL), dried over MgSO4, filtered and concentrated in vacuo. Purified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run) and the corresponding fractions that contained product were lyophilized to afford 45 mg of a white powder as the titled compound. LCMS (M+H)+: 646.3. 1H NMR (500 MHz, CDCl3): δ: 0.73 (d, 3H, J=7.5 Hz), 1.28 (d, 6H, J=6.9 Hz), 2.95 (septet, 1H, J=7.5 Hz), 3.95 (s, 3H), 4.04 (d, 1H, J=7.5 Hz), 4.54-4.59 (m, 4H), 4.64 (d, 1H, J=7.5 Hz), 5.65 (d, 1H, J=8.5 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.73 (s, 2H), 7.90 (s, 1H), 8.13 (d, 1H, J=2.4 Hz), 8.23 (s, 1H). RTA IC50: 5 nM
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[Cl:27])=[O:9])=C.C(O)=O.C(#N)C>CO.ClCCl.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[Cl:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1Cl
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(Br)cc1Cl
Yield: 23.5 %

Procedure:
8-(4-Bromo-2-chloro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (196 mg, 0.43 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane). The appropriate fractions were combined and concentrated to give a residue that was subjected to HPLC (Preparative C18 column, 0.1% formic acid, acetonitrile in water, gradient 5% to 98%, ramp time 20 minutes) to afford the title compound as a pale yellow solid (43 mg, 23%). LCMS (method A): RT=6.71 min, [M+H]+=425/427. 1H NMR (DMSO-d6): 11.68 (1H, s), 10.46 (1H, s), 8.35 (1H, d, J=0.79 Hz), 7.95 (1H, d, J=7.36 Hz), 7.78 (1H, d, J=2.27 Hz), 7.42 (1H, dd, J=8.62, 2.29 Hz), 7.01 (1H, d, J=8.63 Hz), 6.79 (1H, d, J=7.35 Hz), 6.56 (1H, s), 4.69 (1H, s), 3.87 (2H, t, J=4.89 Hz), 3.57 (2H, m).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:14])=[CH:11][C:10](=[O:15])[CH2:9]1>O1CCCC1.C(OCC)C.[Cu]I>[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:1])([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: [Li]C
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(=O)CC(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (6.O g, 0.032 mol) in tetrahydrofuran (120 mL) cooled to 0~C was added a methyllithium solution (45 mL of a 1.4 M solution in diethyl ether, 0.063 mol). After stirring 0.5 hour, 3-(3-methoxy-3-methylbutyl)-5-methylcyclohex-5-en-1-one (2.0 g, 0.0095 mL) in tetrahydrofuran (80 mL) was slowly added. After stirring 2.5 hours, the mixture was added to ice cold dilute hydrochloric acid. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5,5-dimethylcyclohexan-1-one, bp0.5 125-130~C (1.3 g); NMR (CDC13)δ0.9(s,3H), 1.1(s,3H), 1.1(s,6H), 1.2-1.6(m,6H), 1.6-2.5(m,5H), 3.2(s,3H); IR(neat) 2960, 1715, 1365, 1085 cm-1. MS(m/e) 41, 55, 73, 138, 161, 211, 212.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccnc3)nn3ccnc23)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.15 mmol), pyridin-3-ylboronic acid (0.022 g, 0.18 mmol), Pd(dba)2 (0.02 g, 0.035 mmol), X-Phos (0.02 g, 0.042 mmol) and Na2CO3 (0.032 g, 0.3 mmol) in dioxane/H2O (20 mL/2 mL) was stirred at 95° C. for 18 h under N2 atmosphere. The solvent was removed in vacuo and the residue purified by chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(pyridin-3-yl)imidazo[1,2-b]pyridazin-8-amine (0.025 g, 44%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.20 (s, 1H), 8.74-8.72 (m, 2H), 8.32-8.19 (m, 2H), 7.95 (s, 1H), 7.63 (s, 1H), 7.47-7.41 (m, 2H), 6.26 (d, 1H, J=8.1 Hz), 6.07 (d, 1H, J=8.4 Hz), 4.27 (t, 1H, J=6.2 Hz), 3.69-3.64 (m, 1H), 3.50-3.47 (m, 1H), 2.17-2.05 (m, 3H), 1.79 (brs, 1H), 1.27 (d, 3H, J=6.0 Hz). LC/MS: 372 [M+H]+, tR=1.71 min. HPLC: 98.37% at 214 nm, 99.69% at 254 nm, tR=4.70 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>C(Cl)Cl>[CH3:31][C@H:11]1[C:12]2[C:17]([C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]=3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (193 μL, 2.5 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (33 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour, and concentrated to give (5R,7R)-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol as an oil, which was used further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13](=[O:26])[N:14]([CH2:23][CH2:24][CH3:25])[C:15](=[O:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17]=1[NH2:18].O.Cl>C(Cl)Cl.N1C=CC=CC=1.[OH-].[Na+]>[CH2:23]([N:14]1[C:13](=[O:26])[C:12]2[NH:11][C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[N:18][C:17]=2[N:16]([CH2:19][CH2:20][CH3:21])[C:15]1=[O:22])[CH2:24][CH3:25]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc2n(CCC)c1=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
6-Chloronicotinoyl chloride (1.83 g, 10.4 mmol), in CH2Cl2 (20 ml) was added dropwise to a solution of 5,6-diamino-1,3-dipropyluracil (1.808 g, 8 mmol) in dry pyridine (8.2 ml) maintained at 5° C. The reaction was warmed to room temperature and stirred for an additional 3 hours. Water (50 ml) was added to quench the reaction. The solvent was evaporated to afford a dark colored oil. The oil was refluxed for 2 h in 2N NaOH (20 ml). After cooling, the pH was carefully adjusted to 7 with concentrated HCl. A solid formed and was collected and washed with water (20 ml), ether (20 ml) and chloroform(20 ml) to provide an off-white solid (1.9 g). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7](O)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]([F:29])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-(4-Chlorobenzyl)1,3-bis(1,2,4-triazol-1-yl)2-propanol (0.318g) was added to a solution of diethylamino sulphur trifluoride (0.128g) in chloroform (15ml), and the resulting yellow solution was stirred at room temperature for 3.5 hr. The mixture was then poured into water and the organic layer was separated, washed with water, dried, and evaporated to dryness. The yellow oil so obtained was purified by chromatography on a 25cm silica (Merck "Lobar") column, eluting with 3% v/v methanol in chloroform, to give a colourless oil which was crystallised from diethyl ether to give 2-(4-chlorobenzyl)-2-fluoro-1,3-bis(1,2,4-triazol-1-yl) propane, m.p. 161-163°.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=2[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(O)C.C(OCC)(=O)C.[Zn]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:9]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:10]3[C:15]([NH:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COc1ccc2c(C(=O)Oc3ccccc3)c3ccccc3nc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)Nc1ccccc1C2C(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
Ammonium chloride (3.45 g, 64 mmol) and 4.2 g of zinc (64 mmol) were added to an Ar-purged suspension of 0.85 g (2.5 mmol) of the ester from step (c) in 50 mL of ethanol. The mixture was stirred for 2 h, filtered and the solids washed with CH2Cl2. The combined solutions were evaporated to dryness producing a white solid which was dissolved in ethyl acetate and washed with 3×25 mL of water. The product was used without further purification. 1H NMR (CDCl3) δ 3.76 (s, 3H), 5.29 (s, 1H), 6.47-7.36 (m, 12H), 8.21 (br s, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:31]1[C:32]([CH3:38])=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[C:32]=1[CH3:38])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: Cc1c(O)cccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(O)c1C
Temperature: 82 °C
Yield: 43.5 %

Procedure:
Ethyl acrylate (1.16 mL, 10.7 mmol), palladium acetate (60.1 mg, 0.27 mmol), tri-o-tolylphosphine (160 mg, 0.54 mmol) and triethylamine (1.62 mL) were added to a solution of 3-bromo-2-methyl phenol (1 g, 5.35 mmol) in acetonitrile (2.5 mL) under a nitrogen atmosphere. The mixture was heated at 82° C. for 16 hours and cooled. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried under sodium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave trans-3-(3-hydroxy-2-methylphenyl)acrylic acid ethyl ester as a clear oil (480 mg, 43.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:35]([CH3:36])=[CH:34][C:30]2[N:31]=[CH:32][NH:33][C:29]=2[CH:28]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:31]3[C:30]4[CH:34]=[C:35]([CH3:36])[C:27]([CH3:26])=[CH:28][C:29]=4[N:33]=[CH:32]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc4cc(C)c(C)cc43)cc2)cc1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 5,6-dimethylbenzimidazole (40 mg, 0.28 mmol), Cu(OAc)2 (60 mg, 0.33 mmol), triethylamine (115 μl, 0.83 mmol), MS4A (100 mg), and CH2Cl2 (4 ml) was stirred at room temperature for 1 week. After filtration through a bed of celite, the filtrate was diluted with CH2Cl2, and washed with water. The organic fraction was dried over MgSO4 and filtered. After concentration under reduced pressure, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 28 mg (22%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26]C)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:29]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24](=[O:26])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 63 %

Procedure:
A solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (0.92 g, 2.56 mM) in 38 ml THF and 154 mL concentrated aqueous ammonium hydroxide was sonicated for 6 h at 30-40° C. The precipitated solid was filtered, washed with water to afford 0.55 g (63%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.15 (dd, J=8 and 8 Hz, 1H), 7.05 (m, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 6.8 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H)., 2.2 (s, 3H). MS (ES) m/e 328, 345.