Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:19][CH2:18]3)[C:6]=2[CH:31]=1.O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@H:7]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:21][CH2:22]3)[C:6]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)C[C@H](N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Reaction time: 2 h
Yield: 23.3 %

Procedure:
3 G. of the salt of racemic 3-{2-[4-(8-fluoro-10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone with (+)-camphor-10-sulfonic acid monohydrate [(S)-2-oxo-10-bornanesulfonic acid; α546 = +28.0° (water; c = 10%)] in the molar ratio of 1:2 are dissolved in 5 ml. of acetone and allowed to stand at room temperature for 2 hours. After the addition of 5 ml. of acetone, the entire mixture is allowed to stand for an additional 2 hours and then treated with 3 ml. of acetone. The solution is now left to stand at room temperature for 85 hours. The precipitate obtained is subsequently removed by filtration and washed with acetone, and there is obtained the di(camphor-10-sulfonic acid) salt of (+)-(S)-3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone [that is, (+)-(S)-3-{ 2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin- 10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone-(S)-2-oxo-10-bornanesulfonate (1:2)], from which the base is liberated by treatment with aqueous sodium hydroxide. The first crystallizate is obtained in a purity of about 84% and in a yield of 23.3% based on the racemate used (that is, 46.6% of theory). αD =+9.5° (chloroform; c =1%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1
Reactant: CO
Reactant: NC(CC(=O)O)c1cncc(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
9.54 g (38.93 mmol) 3-amino-3-(5-bromopyridin-3-yl)propionic acid were suspended in 158 ml methanol and the mixture cooled to 0° C. 4.26 ml (58.39 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over silica gel (dichloromethane/ethanol 100/0-50/50) gave 5.84 g (52%) 3-amino-3-(5-bromopyridin-3-yl)-propionic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][N:17]([O:18][CH3:19])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1Cl
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (97% yield): mp 127-128° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.95 (2H, s, NCH2), 6.41 (1H, s, CH), 6.96 (1H, m, aromatic), 7.13 (1H, dd, J=2.5 Hz and J=8.7 Hz, aromatic), 7.38 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C, 52.49; H, 4.15; N, 3.76.
Reaction SMILES: B.C1C[O:5]CC1.C1COCC1.[C:12]1([CH3:46])[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[CH:34]=[CH:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:21]3=[N:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1.OO.[OH-].[Na+]>>[OH:5][CH:33]1[CH2:32][N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:21]2=[N:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([CH3:46])=[CH:17][CH:16]=3)[N:19]=[C:20]2[CH2:34]1
Reactant: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: CCOC(=O)CCCCCCN1CC(O)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1M BH3.THF in THF (3.66 ml, 3.66 mmol) was added dropwise to Ethyl 7-(2,3-dip-tolylpyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (1.145 g, 2.438 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0-5° C. using an ice bath. The mixture was treated with 35% H2O2 (1.067 ml, 12.19 mmol) followed by 2M NaOH (6.10 ml, 12.19 mmol). The mixture was allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The reaction mixture was washed with water (25 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts were combined, dried over MgSO4, filtered and the filtrate concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification by chromatography on silica eluting with DCM/MeOH to afford the title compound;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][C:23]=1[CH2:29][NH2:30]>CCCCO>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc(C)c(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(C)c(CNc2nc(F)nc3[nH]cnc23)cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.83 g, 4.9 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (4,6-dimethylpyridine-3-yl)methanamine (1 g, 7.35 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 2 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.86 g (65%); δH (250 MHz, CDCl3) 2.35 (3 H, s, CH3), 2.39 (3 H, s, CH3), 4.61 (2 H, s, br, NHCH2), 7.07 (1 H, s, ArH), 8.13 (1 H, s, ArH), 8.33 (1 H, s, ArH), 8.69 (1 H, s, br, NH); δC (250 MHz, CDCl3) 161.2 (C), 158.57 (C), 156.08 (C), 150 (C), 148.08 (CH), 148.14 (CH), 147.9 (CH), 145.93 (C), 129.92 (C), 129.76 (C), 124.37 (CH), 41.7 (CH2), 23.17 (CH3), 18.14 (CH3); m/z 273.2 (M+H)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH2:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg)(EXAMPLE 31) in ethyl acetate (500 μl) was added rhodium on carbon (5 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was removed in vacuo to give the title compound (20 mg). MASS (FAB) 940 (M+Li); Partial 1H NMR δ: 7.18 (s,1H); 7.16 (d, J=9 Hz, 1H); 6.96 (d, J=3Hz, 1H); 6.92 (dd, J=9,3Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.55 (brd, J=4 Hz, 1H); 3.72 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16][OH:17])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].ClCCl.[N:25]1[C:34]2[C:29](=[CH:30][C:31]([C:35](Cl)=[O:36])=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[N:25]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([O:17][CH2:16][C:14]3[NH:13][C:10]4=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]5[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=5[Br:1])[CH:8]=[C:9]4[CH:15]=3)=[O:36])=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1
Reactant: O=C(Nc1cnc2[nH]c(CO)cc2c1)c1ccccc1Br
Reactant: O=C(Cl)c1ccc2nccnc2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1cc2cc(NC(=O)c3ccccc3Br)cnc2[nH]1)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
A flask is charged successively with 50 mg (0.14 mmol) of 2-bromo-N-(2-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide AT2-2BF2 (example 16), 5 mL of dichloromethane, 30 mg (0.15 mmol) of 6-quinoxalinecarbonyl chloride and 30 μL (0.22 mmol) of triethylamine. The solution is stirred at room temperature for 18 hours and then diluted in 60 mL of ethyl acetate, washed with 10 mL of saturated solution of sodium bicarbonate, 10 mL of water, and 10 mL of saturated solution of sodium chloride. The organic phase is then dried over sodium sulphate and evaporated under reduced pressure. The raw product is then purified by silica gel chromatography (ethyl acetate/petroleum ether eluent). 14 mg of a yellow solid is obtained (24%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:77]1[CH:82]=[CH:81][C:80](B2OC(C)(C)C(C)(C)O2)=[C:79]([CH3:92])[CH:78]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([O:72][CH2:73][O:74][CH3:75])([C:68]([F:71])([F:70])[F:69])[C:64]([F:67])([F:66])[F:65])=[C:57]([CH3:76])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:80]2[CH:81]=[CH:82][C:77]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]([O:72][CH2:73][O:74][CH3:75])([C:68]([F:71])([F:70])[F:69])[C:64]([F:67])([F:66])[F:65])=[C:57]([CH3:76])[CH:56]=3)[CH2:50][CH3:51])=[CH:78][C:79]=2[CH3:92])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 28 mg, 0.122 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.6 mg, 0.016 mmol), potassium phosphate (52 mg, 0.246 mmol) and water (0.1 mL) were added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 50 mg, 0.082 mmol) in toluene (1 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (44.9 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][OH:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][O:5][C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]1[CH2:32][CH3:33])=[O:30]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: OCc1c(F)cc(OCC2CC2)cc1Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCC2CC2)cc1Cl
Yield: 95 %

Procedure:
This compound was prepared from 2-Chloro-4-cyclopropylmethoxy-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (580 mg; 95%); MS (ISP): 488.4 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]1(B(O)O)[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].ClCCl>C(OCCO)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]3)[C:19]2[C:28]3=[C:27]4[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[C:26]4[CH:25]=[CH:24][C:23]3=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-Bromo-2-methylquinoline (4.5; 20 mmole) was dissolved in 2-ethoxy ethanol (30 ml) and to the magnetically stirred solution under nitrogen was added tetrakis(triphenyl phosphine) palladium (1 g; 0.9 mmole). After 5 minutes stirring at room temperature, 1-pyreneboronic acid (5.0 g; 20 mmole) was added followed by 2-ethoxyethanol (10 ml). Sodium hydrogencarbonate (10 g; 94 mmole) in water (60 ml) was added all at once and the reaction mixture was stirred and heated under nitrogen atmosphere at 90° C. for 18 h. The reaction mixture was allowed to cool, dichloromethane (100 ml) was added and the reaction mixture was filtered through a layer of silica gel. To the filtrate further dichloromethane (50 ml) was added and extracted with de-ionised water (2×100 ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent removed to give the required product. The product was dried under vacuum at 80° C., Yield 4.5 g (67%). Mp 133° C. (DSC, onset). Elemental analysis: Found C, 90.80; H, 5.09; N, 4.32; C26H17N requires C, 90.93; H, 4.99; and N, 4.08%.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][OH:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH3:25][S:26]([O:17][CH2:16][CH2:15][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:28])=[O:27]
Reactant: OCCN1c2ccccc2Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reaction time: 3 h
Yield: 235.7 %

Procedure:
To a solution of 2-(10H-phenoxazin-10-yl)-1-ethanol (4.6 g, 20.28 mmol) in dichloromethane (20 ml) was added triethylamine (1.06 g, 10.56 mmol) under an atmosphere of nitrogen at 25° C. Methanesulfonyl chloride (0.90 g, 7.92 mmol) was added to the above reaction mixture at 0° C. and stirring was continued for further 3 h at 25° C. Water (50 ml) was added, and aqueous phase extracted with chloroform (2×25 ml). The combined organic phases were washed with water (25 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was triturated with petroleum ether to afford the title compound (5.7 g, 92%) as a solid. mp: 81-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:9][C:6]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]2[C:5]=1[CH:19]=[CH:14][CH:15]=[N:4]2
Reactant: Nc1cc(F)ccc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Fc1ccc(Cl)c2ncccc12
Temperature: 140 °C
Yield: 59.3 %

Procedure:
To a mixture of (5.0 g) 2-chloro-5-fluoroaniline (commercially available, 6.0 g), glycerol (6.0 g) and m-nitrobenzene sulfonic acid sodium salt (11.0 g), was added 20 ml of 70% sulfuric acid dropwise. The reaction temperature was raised to 140° C. for 2 hr. The mixture was then cooled, poured on ice water and filtered through celite. The filtrate was neutralized with NaOH and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2 to give 3.7 g of the desired product of a yellow solid; MP=74-76° C.; MS (ES) m/z (relative intensity): 182 (M+H)+ (100).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[N:33](S(C4C=CC(C)=CC=4)(=O)=O)[C:34]([C:36]4[C:44]5[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([O:45][CH3:46])[CH:43]=5)[N:38]([CH3:49])[CH:37]=4)=[CH:35][C:28]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>O1CCCC1.O>[CH:19]1([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][C:34]([C:36]4[C:44]5[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([O:45][CH3:46])[CH:43]=5)[N:38]([CH3:49])[CH:37]=4)=[CH:35][C:28]=23)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1cc2c(-c3cc4c(CNC5CCCCC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(-c3cc4c(CNC5CCCCC5)ccnc4[nH]3)cn(C)c2cc1OC
Reaction time: 15 h
Yield: 28.3 %

Procedure:
1 cm3 of a 1M solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran is added, at a temperature in the region of 20° C., to a solution of 0.14 g of cyclohexyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 10 cm3 of tetrahydrofuran. The reaction medium is stirred at this same temperature for 15 hours, and then refluxed for 24 hours. After cooling, the reaction medium is evaporated to dryness under reduced pressure. 4 cm3 of water are added. The solid formed is filtered off on a sinter funnel, and washed with water and then with ethyl ether. The solid obtained is taken up in water and the medium is basified to pH 10 with 0.1N sodium hydroxide. The product is extracted five times with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.029 g of cyclohexyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 15 h
Yield: 79.6 %

Procedure:
4-Bromo-2-ethyl-aniline (2 mL, 14 mmol) dissolved in anhydrous pyridine (35 mL) at toom temperature was treated with methylsulfonyl chloride (1.3 mL, 16.8 mmol). The reaction was stirred at that temperature for 15 hours before it was diluted with EtOAc. The mixture was washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with flash chromatography (SiO2, 5-30% EtOAc in hexanes) to afford the desired product (3.1 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 2.61-2.68 (m, 2H), 3.02 (s, 3H), 6.36 (s, 1H), 7.36-7.39 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=2[CH:7]=1)=[O:18]
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=C(Cl)CCCCCl
Product: CC1(C)Cc2cc(C(=O)CCCCCl)ccc2O1

Procedure:
Using 2,2-dimethyl-2,3-dihydro-1-benzofuran (3.0 g) and 5-chlorovaleryl chloride (3.4 g) according to the same method as that of Reference Example 1, the title compound was obtained as a fine yellow oil (3.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1Br)[CH2:8][CH2:7][CH2:6]2.[Li]CCCC.C([O:20][B:21](OCC)[O:22]CC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:11]=1[B:21]([OH:22])[OH:20]
Reactant: CCOB(OCC)OCC
Reactant: COc1cc2c(cc1Br)CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1B(O)O)CCC2
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A dry 250 mL round bottom flask was charged with 6-bromo-2,3-dihydro-1H-inden-5-yl methyl ether (9.38 grams, 41.27 mmol) and placed under high vacuum for 18 hours. THF (51.6 mL) was added via syringe. The solution was homogeneous and clear. The reaction was cooled with a dry ice/acetone bath for 15 minutes, then n-BuLi was added semi-dropwise. A color change to pale yellow was observed. The reaction was stirred at −78° C. for 1 hour, followed by drop-wise addition of triethylborate (7.73 mL, 45.43 mmol). After continued stirring and cooling at −78° C. for 2 hours, the reaction was quenched with 10% aq. HCl (50 mL, 3M), the cooling bath was removed, and the reaction was allowed to warm to ambient temperature. The reaction was poured in water and extracted two times with ethyl acetate. The organics were combined, dried with MgSO4, filtered and concentrated to 8.0 grams of 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid as a white, somewhat tacky, solid. The solid turned blue over 48 hours. The boronic acid was used without further purification.