Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]([F:15])[F:14])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-bromophenol (available from Sigma Aldrich) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (available from Sigma Aldrich) (2.82 g, 18.49 mmol) and cesium carbonate (4.82 g, 14.79 mmol). The reaction mixture was heated at 100° C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T7.1 as an oil that was used without further purification (yield 61%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(CCF)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCF)cc3)cc2)C1
Yield: 5.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(2-fluoro-ethyl)-benzenesulfonyl chloride (117 mg, 0.52 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (11 mg, 6%) as a colourless gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:56][CH:57]([F:60])[CH2:58][OH:59]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][CH:57]([F:60])[CH2:58][O:59][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: OCC(F)F
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 0.297 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.009 g, 0.025 mmol), and cesium carbonate (0.163 g, 0.5 mmol) in toluene (5 mL) was treated with 2,2-difluoro ethanol (0.05 mL, 0.6 mmol) and stirred at 110° C. for 12 h. After this time the solvent was evaporated and silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded the desired product (0.055 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.14-4.26 (m, 4H), 4.72 (s, 2H), 5.92-6.32 (m, 1H), 6.82 (s, 1H), 6.97 (s, 1H), 7.23-7.33 (m, 4H). GC-MS: m/z 371 (M)+, 336 (M−35)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C=Nc1ccc(F)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(F)cc4)nc23)CC1
Yield: 73.7 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.096 mL (0.85 mMol) 4-fluorophenyl isocyanate, 0.176 gm (74%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from methanol. m.p.=245.8° C. (dec.) MS(m/e): 367(M+) Calculated for C20H22N5OF: Theory: C, 65.38; H, 6.03; N, 19.06. Found: C, 65.36; H, 6.23; N, 18.91.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 26.8 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (304.2 mg, 0.60 mmol, 1.00 equiv), cyclopropanecarbaldehyde (210 mg, 3 mmol, 5 equiv), piperidine (102 mg, 1.20 mmol, 2 equiv) in EtOH (20 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum. Then concentrated and purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 90 mg (22.3%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560 (M-TFA+1) H-NMR (400 MHz, CDCl3, ppm): 11.94 (brs, 1H), 8.27 (s, 1H), 7.62-7.58 (m, 1H), 7.19-7.13 (m, 2H), 7.04-6.98 (m, 2H), 6.91 (d, J=11.2 Hz, 1H), 6.81 (d, J=11.2 Hz, 1H), 6.01 (brs, 1H), 4.96-4.86 (m, 1H), 4.76-4.62 (m, 2H), 3.71-3.62 (m, 1H), 3.61-3.45 (m, 1H), 2.12-1.82 (m, 5H), 1.30-1.28 (m, 2H), 0.94-0.89 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[CH:9]=[CH:8]1.[CH:20](OC)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:21][CH:20]=[C:6]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[CH:9]=[CH:8]1)[C:5]([O:4][CH3:3])=[O:19]
Reactant: COC=O
Reactant: CCOc1ccc2ccn(CC(=O)OC)c2c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccn(C(=CO)C(=O)OC)c2c1
Yield: 63.8 %

Procedure:
Sodium hydride (0.58 g, 50% in oil, 12 mmol) was washed with petrol (60°-80° C.) and suspended in DMF (20 ml). To this, with vigorous stirring, was added dropwise, a solution of the crude methyl(6-ethoxyindol-1-yl)acetate (1.4 g, 6 mmol) and methyl formate (1.8 ml, 30 mmol) in DMF (10 ml) at room temperature. After 3 hours the reaction mixture was poured into 10% aqueous potassium carbonate (100 ml), washed with ether (2×100 ml), neutralised with concentrated hydrochloric acid and extracted with ether (2×100 ml). These extracts were washed with brine, dried and concentrated to give methyl 3-hydroxy-2-(6-ethoxyindol-1-yl)acrylate (1.0 g, 63% yield) as an orange oil.
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10]C)=[C:5]([CH3:12])[C:4]=1[CH2:13][CH:14]([NH2:16])[CH3:15].[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[OH:10][C:6]1[C:5]([CH3:12])=[C:4]2[C:3](=[C:8]([CH3:9])[CH:7]=1)[NH:16][CH:14]([CH3:15])[CH2:13]2
Reactant: COc1cc(C)c(OC)c(CC(C)N)c1C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(O)c(C)c2c1NC(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To the solution of 1-(2,5-dimethoxy-3,6-dimethylphenyl)-2-propanamine (2.2 g, 9.4 mmol) in acetonitrile (10 ml) was added dropwise a solution of cerium (IV) diammonium nitrate (10.0 g, 18.2 mmol) in acetonitrile (20 ml) and water (20 ml) with cooling on ice, and stirred at room temperature for 2 hours. The reaction mixture was diluted with water, neutralized with sodium hydrogen carbonate, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid. The solid was dissolved in ethyl acetate, combined with an aqueous solution of sodium hydrosulfite and shaken to precipitate a solid, which was collected by filtration to obtain 1.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2Br)=[O:11])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:12]=3[C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(F)ccc1O)c1ccsc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccc(F)cc1NC2=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a solution of N-(3-fluoro-6-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 140° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into diluted hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, dissolved in chloroform, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=99.5:0.5). The solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the precipitated crystals were collected by filtration to give 7-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (350 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cc(F)c(F)c(C)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
To 2,4,5-trifluoro-3-methyl-N-acetylaniline (1.94 g) is added conc. sulfuric acid (19 ml) and the mixture is cooled to 0° C. Thereto potassium nitrate (2 g) is added below 20° C. and the mixture is stirred for 15 minutes. The reaction mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitro-N-acetylaniline (2.08 g), as white crystals.
Reaction SMILES: C(O[C:6](=[O:47])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][C:22](=[O:43])[NH:23][C@H:24]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)[N:16]=[C:15]([NH2:44])[N:14]=2)[C:10]([CH3:45])=[CH:9][C:8]=1[CH3:46])(C)(C)C.FC(F)(F)C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.O>[NH2:44][C:15]1[N:14]=[C:13]2[CH:18]=[C:17]([N:16]=1)[S:19][CH2:20][CH2:21][C:22](=[O:43])[NH:23][C@H:24]([C:35]([N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)=[O:36])[CH2:25][CH2:26][NH:27][C:6](=[O:47])[C:7]1=[CH:12][C:11]2=[C:10]([CH3:45])[CH:9]=[C:8]1[CH3:46]
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N3CCOCC3)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C)c2cc1C(=O)NCC[C@@H](C(=O)N1CCOCC1)NC(=O)CCSc1cc-2nc(N)n1
Reaction time: 2 h
Yield: 63.2 %

Procedure:
5-(2-Amino-6-{2-[(S)-3-tert-butoxycarbonylamino-1-(morpholine-4-carbonyl) propylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (79 mg) obtained in Step 3 above was dissolved in dichloromethane (1.5 ml), and then trifluoroacetic acid (0.5 ml) was added thereto at room temperature. The reaction solution was stirred for two hours, and then concentrated under reduced pressure. Toluene (3 ml) was added to the obtained residue, and then concentrated under reduced pressure. The resulting pale yellow oily material was dissolved in a mixture of N,N-dimethylformamide (29 ml) and tetrahydrofuran (29 ml), and then O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (55.8 mg, 0.142 mmol) and diisopropylethylamine (0.102 ml) were added thereto at room temperature. The reaction solution was stirred for one hour. Water (20 ml) was added to the reaction solution, and concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (30 ml) was added to the resulting residue and then extracted twice with ethyl acetate (30 ml). The ethyl acetate solution was washed twice with a saturated aqueous sodium chloride solution (20 ml) and a saturated aqueous sodium bicarbonate solution (20 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography (developing solvent: A, acetonitrile containing 0.05% trifluoroacetic acid; B, 0.05% aqueous trifluoroacetic acid solution; gradient condition: B, 1% (0 min)→1% (1 min)→30% (7 min)→95% (8 min)→95% (9 min)→1% (10 min); flow rate, 35 ml/min; column, Waters, SunFire PrepC18, 5 μm, 30×50 mm). A fraction containing the material of interest was neutralized with solid-supported tetraalkyl ammonium carbonate (Polymer Laboratories, PL-HCO3 MP-Resin) to yield (S)-4-amino-18,20-dimethyl-12-(morpholine-4-carbonyl)-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2,4,6(22),17(21),18-hexaene-10,16-dione (Compound 70)(37 mg) as a white solid material.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[C:48]2([CH2:66][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:64]2)[C:47]1=[O:74].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@@H:11]4[CH2:12][C:13](=[O:16])[NH:14][CH2:15]4)[CH3:10])=[N:7][C:2]([C:52]4[CH:53]=[C:54]5[C:49]([C:48]6([CH2:64][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66]6)[C:47](=[O:74])[N:46]5[CH3:45])=[CH:50][CH:51]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CN1C(=O)C2(CN(C(=O)OC(C)(C)C)C2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C(=O)OC(C)(C)C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial, a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 2.71 (50 mg, 0.14 mmol), tert-butyl 1′-methyl-2′-oxo-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indoline]-1-carboxylate 7.59 (68 mg, 0.16 mmol), cesium carbonate (140 mg, 0.43 mmol), and PEPPSI-IPr catalyst (8.2 mg, 0.01 mmol) were taken up in dimethoxyethane (1.8 mL) and water (0.9 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for 90 minutes in a microwave reactor. After cooling to rt, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-10% methanol/dichloromethane) to yield tert-butyl 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 3.84 (53 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H37N6O5: 573.27; found: 573.27.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@H:7]1[CH2:12][C@H:11]2[C@:9]([CH3:13])([CH2:10]2)[C:8]1([CH3:15])[CH3:14])/[CH2:3][OH:4].[CH3:16][Mg]Cl.O1CCCC1.BrCBr.C([Mg]Cl)(C)(C)C>>[CH3:1][C:2]1([CH2:3][OH:4])[CH2:16][CH:5]1[CH2:6][C@H:7]1[CH2:12][C@H:11]2[C@:9]([CH3:13])([CH2:10]2)[C:8]1([CH3:15])[CH3:14]
Reactant: C[Mg]Cl
Reactant: C/C(=C\C[C@H]1C[C@@H]2C[C@]2(C)C1(C)C)CO
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: BrCBr
Product: CC1(CO)CC1C[C@H]1C[C@@H]2C[C@]2(C)C1(C)C
Temperature: 25 °C

Procedure:
System B: (E)-2-methyl-4-((1S,3S,5R)-1,2,2-trimethylbicyclo-[3.1.0]hexan-3-yl)but-2-en-1-ol (5 g, 24 mmol) (F. Schröder, WO 2006066436, priority 20.12.2005 to Givaudan) is added undercooling and stirring to methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol) under nitrogen. Dibromomethane and tert-butyl magnesium chloride are added at a temperature of 10°-20° C. The dibromomethane and tert-butyl magnesium chloride are each added in 3 portions, one portion of dibromomethane (4.2 g, 24 mmol) followed by a portion of tert-butyl-magnesium chloride (12 ml, 24 mmol). After the addition of each pair of portions (72 mmol) the mixture is stirred for an appropriate time at room temperature. When complete or nearly complete conversion is reached, as checked by GC, the mixture is quenched by addition of conc. NH4Cl. Tert-Butyl methyl ether extraction, washing of the organic phase with H2O until pH 7, drying over MgSO4 and concentration gives 16.6 g of an an oily residue, which is bulb-to bulb-distilled at 120° C./0.07 Ton giving 4.7 g (89%) of Javanol (dr=1:1), whose analytical data are consistent with the ones described for this compound in the literature (J. A. Bajgrowicz, G. Frater, EP 801049, priority 9.4.1997 to Givaudan-Roure).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[CH:6]=1.[OH-].[Na+].C(#N)C>C(O)C.C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(C)=O)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a solution of [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (112 mg, 0.29 mmol) in ethanol (3 mL) and THF (3 mL) was added a sodium hydroxide solution (586 uL, 1.0 N) at room temperature. The resulting clear solution was stirred for 4 h. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of drying agent and concentration of the solvent under vacuum gave a solid which was treated with hot acetonitrile. After cooling in the refrigerator, the solids were collected by filtration and washed with acetonitrile to give [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid (65 mg, 60.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.50 (s, 1 H), 10.13 (s, 1 H), 7.93 (d, J=8.8 Hz, 1 H), 7.84 (s, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.45 (dd, J=8.8, 1.8 Hz, 1 H), 7.15 (m, 3 H), 3.84 (s, 2 H), 2.10 (br. s., 3 H), 2.09 (br. s., 3 H). HRMS (ES+) calcd. for C21H19ClNO3 [(M+H)+] 368.1048, obsd. 368.1049.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=O)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:27]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
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: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
HATU (411 mg, 1.08 mmol) was added to a solution of 4-chloro-2-pyridinecarboxylic acid (142 mg, 0.90 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.394 ml, 2.25 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (333 mg, 1.082 mmol) was then added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organics were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave a pale yellow gum, shown to be impure by LCMS and NMR analysis. Further purification by MDAP gave the title compound as a colourless glass (159 mg).