Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.II.Cl>C1COCC1.CCOCC.[Zn]>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)C(O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-bromophenylacetate (473 mg; 2.065 mmol) and 4-methylbenzaldehyde (188 mg, 1.57 mmol) in dry THF (5 mL) under N2 was added powdered zinc (201 mg, 3.09 mmol). After stirring at reflux for 10 min, a few crystals of iodine were added. The mixture was refluxed under N2 for 4 hours, then allowed to stand at room temperature overnight. The next day the mixture was diluted in Et2O and 1N HCl was added. The biphasic mixture was stirred until the zinc had completely dissolved in the aqueous layer. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue which contained two diastereomers (Rf=0.22, 0.17 in 15% EtOAc/hexane), was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane. A total of 283 mg (67%) of both diastereomers was isolated. The 300 MHz 1H NMR spectra of each diastereomer was consistent with its structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)(Cl)Cl>[CH2:18]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 924.2 %

Procedure:
To a solution of methyl piperidine-4-carboxylate (10.00 g, 6.4 mmol) and triethylamine (10.32 g, 10.2 mmol) in CHCl3 (100 mL), benzyl bromide (14.69 g, 8.6 mmol) was added under argon atmosphere while cooling with a water and ice bath. The mixture was stirred at room temperature overnight. CHCl3 and water were added and the two phases were separated. The aqueous phase was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 13.80 g of the desired compound as an orange solid (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ccc([N+](=O)[O-])c(Br)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a solution of N-(6-bromopyridin-2-yl)acetamide (9.0 g, 40 mmol) in H2SO4 (100 mL) was added HNO3 (69%, 5.5 g, 60 mmol) drop-wise at 0° C. The mixture was stirred at this temperature for 4 hours, and was then poured into ice-water. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 6-bromo-5-nitropyridin-2-amine (7.5 g, 82%). 1H NMR (400 MHz, DMSO) □ 8.10 (d, J=8.8 Hz, 1H), 7.73 (brs, 2H), 6.46 (d, J=8.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]#[N:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]3[NH:23][N:22]=[N:21][N:16]=3)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C1(CCCC1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(OCc3nnn[nH]3)c(Cl)c2Cl)CC12CCCC2

Procedure:
The title compound is prepared following substantially the same procedure described in Example 5, Step G, using the following substances: [1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)-5'-yloxy]acetonitrile (5.3 g.), sodium azide (1.44 g.), ammonium chloride (1.14 g.) and dimethylformamide (35 ml.). This procedure affords 5.0 g. (83%) of 5-[1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)5'-yloxymethyl]tetrazole which after recrystallization from acetonitrile melts at 191°C.
Reaction SMILES: FC1C=CC(I)=CC=1C(Cl)=O.BrC1C=CC(OC)=CC=1OC(F)(F)F.ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:34][C:35]1[C:36]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:37][C:38]([O:51]C)=[C:39]([C:41]([C:43]2[CH:48]=[C:47]([I:49])[CH:46]=[CH:45][C:44]=2F)=[O:42])[CH:40]=1.C(O)C.CO.C[O-].[Na+].C1C2C(=O)C3C(=CC=CC=3)OC=2C=CC=1>>[Br:34][C:35]1[C:36]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:37][C:38]2[O:51][C:44]3[C:43](=[CH:48][C:47]([I:49])=[CH:46][CH:45]=3)[C:41](=[O:42])[C:39]=2[CH:40]=1
Reactant: COc1cc(OC(F)(F)F)c(Br)cc1C(=O)c1cc(I)ccc1F
Agent: COc1ccc(Br)c(OC(F)(F)F)c1
Agent: C[O-]
Agent: O=C(Cl)c1cc(I)ccc1F
Solvent: ClCCCl
Solvent: CCO
Solvent: CO
Product: O=c1c2cc(I)ccc2oc2cc(OC(F)(F)F)c(Br)cc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
In a 500 mL flask, 2-fluoro-5-iodobenzoyl chloride (6.06 g, 21.3 mmol) and 1-bromo-4-methoxy-2-(trifluoromethoxy)benzene (5.77 g, 21.3 mmol) were dissolved in 1,2-dichloroethane (50.7 mL, 21.3 mmol) and the solution was cooled to 0 to 5° C. Aluminum chloride (2.84 g, 21.3 mmol) was added portionwise to the solution. The red solution was warmed to rt. After 2 h, LCMS showed mainly (5-bromo-2-methoxy-4-(trifluoromethoxy)phenyl)(2-fluoro-5-iodophenyl)methanone. The whole was refluxed for 1 h. LCMS showed complete consumption of (5-bromo-2-methoxy-4-(trifluoromethoxy)phenyl)(2-fluoro-5-iodophenyl)methanone. The reaction was cooled to rt. Ice (5-10 chips) and concentrated HCl (2 mL) was added until pH ˜1. The whole was stirred at rt for 30 min. The resulting slurry was extracted with ether (3×80 mL). The organic layer was washed with water, dried over MgSO4, filtered, and concentrated to afford a semi-black solid that was carried on to the next step. The crude was added to a mixture of ethanol (85 mL, 21.3 mmol), methanol (30.4 mL, 21.3 mmol), and sodium methoxide (2.30 g, 42.6 mmol) at rt. After refluxing for 1 h, LCMS showed mainly the cyclized xanthenone product. The whole was cooled to rt and concentrated. Water (80 mL) and EtOAc (120 mL) was added. The product was extracted with EtOAc (2×80 mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated. Trituration with hexanes gave 2-bromo-7-iodo-3-(trifluoromethoxy)-9H-xanthen-9-one (2.94 g, 6.06 mmol, 29% yield) as a gray solid. LCMS (ESI) calcd for C14H5BrF3IO3: [M]+=484. Found [M+H]+=485.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.CCN(CC)CC.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][C:47]1=[O:52]>C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[C:47](=[O:52])[CH2:48]4)=[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Reactant: CN1CCNCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)C(=O)C4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 368 mg, 0.657 mmol) in DCM (2.7 ml) at room temperature was added NEt3 (0.319 ml, 2.301 mmol) followed by 1-methylpiperazin-2-one (120 mg, 1.052 mmol). The reaction mixture was stirred at room temperature for 2 h and partitioned between DCM and water. The water layer was extracted multiple times with DCM, the combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid. (UPLC-MS 3) tR 0.87 min; ESI-MS 553.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.75 (s, 1H), 8.20 (s, 1H), 7.64 (br s, 1H), 7.58 (s, 1H), 5.56 (s, 1H), 5.23 (d, 1H), 4.06-4.01 (m, 2H), 3.70 (br s, 2H), 3.63 (t, 2H), 3.50-3.42 (m, 8H), 3.40 (s, 3H), 3.31 (br s, 2H), 3.14 (br s, 2H), 2.96 (br s, 3H), 2.87-2.80 (m, 2H), 2.71 (br s, 2H), 2.03-1.96 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)CC)(=O)[CH2:14][CH3:15].[OH-].[Na+]>Cl>[CH2:14]([C:15]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:13]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1cnc2ccccc2c1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2cnc3ccccc3c2s1
Yield: 90 %

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline and 85 ml of propionic anhydride is first slowly heated to boiling and then refluxed for one hour and a half. The reaction mixture is added dropwise to 800 ml of 1% aqueous hydrochloric acid under vigorous stirring. The homogenous solution is made alkaline to pH 10 by adding sodium hydroxide solution and extracted three times with 200 ml of benzene each. The benzene solution is evaporated. Thus 19.26 g of 2-ethylthiazolo[4,5-c]quinoline are obtained, yield 90%, m.p.: 48°-49° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Product: COc1ccc(Nc2nc3c(Nc4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1

Procedure:
N(8)-(4-Methanesulfonyl-phenyl)-N(2)-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 4-methanesulfonyl-phenylamine (33.0 mg, 0.193 mmol) in a manner analogous to Example 30. The title compound was isolated as a brown foam (0.013 g, 20%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.08 (d, J=6.1 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.35-7.30 (m, 3H), 6.95-6.90 (m, 3H), 6.85-6.80 (m, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.07 (s, 3H). MS=410 (MH)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)(=[O:13])=[O:12].[ClH:37]>C(OCC)C>[ClH:37].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18]1[CH2:24][CH:25]3[NH:29][CH:28]([C:17]2=1)[CH2:27][CH2:26]3)(=[O:12])=[O:13]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc5ccccc5c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc5ccccc5c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) followed by semi-preparative HPLC. The free base was treated with 1.25 M HCl in methanol (0.5 mL) and lyophilized to give 2-(2-napthyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (41 mg, 45%, AUC HPLC >99%) as an off-white solid: mp 220-222° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.42 (br s, 1H), 9.16 (br s, 1H), 8.66 (d, J=1.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.19 (dd, J=8.0 Hz, 2.1 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.01 (dd, J=8.0 Hz, 2.1 Hz, 1H), 7.88 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.64-7.75 (m, 4H), 5.36 (d, J=3.9 Hz, 1H), 4.47 (br s, 1H), 3.67 (s, 3H), 3.30-3.42 (m, 1H), 3.00 (d, J=17.1 Hz, 1H), 2.18-2.34 (m, 2H), 2.05-2.15 (m, 1H), 1.70-1.87 (m, 1H); ESI MS m/z 403 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)c(Cl)c1)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a solution of 300 mg (1.68 mmol) of benzo[b]thiophene-2-carboxylic acid in DMF (8 ml) were added 320 mg (1.68 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine and 595 mg (1.85 mmol) of TBTU. After 10 min 1.47 ml (8.42 mmol) of N,N-diisopropylethyl amine were added and the reaction mixture was stirred over night at RT. Then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, sat. NaHCO3 solution, 1N HCl and again with brine. The organic layer was then dried (MgSO4) and concentrated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 9:1) to yield 515 mg (87%) of benzo[b]thiophene-2-carboxylic acid[2-(3,4-dichloro-phenyl)-ethyl]-amide as a white solid. MS (ISP) 350.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Li].CN(C)[CH:30]=[O:31].C(O)(=O)C>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH:30]=[O:31])=[C:14]([F:19])[C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1C=O
Yield: 40.9 %

Procedure:
In a manner similar to the method described in example 52a, tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane (14.3 g, 47 mmol) prepared in example 132a was reacted with lithium diisopropylamine (34 mL, 1.8 M in THF, 61 mmol), N,N-dimethyl-formamide (4.7 mL, 61 mmol) and quenched with acetic acid (14 g, 234 mmol) in tetrahydrofuran to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde as a white solid (Yield: 6.4 g, 41%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH2:21](Br)[C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1.S(=O)(=O)(O)O.N1C=CC=CC=1>COCCOC.CCOCC>[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1)[CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CC(C)CCOCCCCOCCCCCCO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC(C)CCOCCCCOCCCCCCOCc1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
0.60 g (0.020 mol) of 80% sodium hydride dispersion are added by portions, at 20°, under nitrogen and while stirring, to 4.02 g (0.0155 mol) of 6-(4-Isopentyloxy-butyloxy)-hexanol in 60 cc of absolute 1,2-dimethoxy-ethane. The mixture is stirred at 60° over the course of 2 hours, cooled to 0° and a solution of 3.65 g (0.017 mol) of piperonyl bromide in 40 cc of absolute 1,2-dimethoxy ethane is added dropwise over the course of 10 minutes. The mixture is stirred at 20° for 3 hours and then at 40° for 20 hours, neutralized with 6N sulphuric acid and together with 1.35 g (0.017 mol) of pyridine heated to 60° over the course of 2 further hours. The reaction product is taken up in ether, washed with water, 6N sulphuric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel with hexane/acetone (98:2) and (96:4), [6-(4-Isopentyloxybutyloxy)-hexyl]-piperonyl ether is obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)cccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 2-amino-6-nitrobenzoic acid (11.9 g, 65.3 mmol), methyl p-toluenesulfonate (15.1 g, 81.1 mmol) and triethylamine (6.60 g, 65.3 mmol) in DMF (170 ml) was stirred under N2 at 60° for 18 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was dissolved in ETOAc and washed with a saturated solution of NaHCO3 followed by a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2SO4) , filtered and concentrated under reduced pressure. Flash chromatography over silica gel and elution with 50% toluene-50% CHCl3 gave methyl 2-amino-6-nitrobenzoate benzote (7.6 g, 59.4%), m.p. 105°-107°.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(Cl)ccc1Br
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3-oxazolidin-2-one (44 mg, 0.085 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78, 23 mg, 0.11 mmol), potassium carbonate (25 mg, 0.18 mmol) and catalytic amount of PdOAc in a 4:1 mixture of acetone/water was heated to reflux for 1 h. Acetone was removed and water was added. The organic was extracted with methylene chloride (3×15 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained as a solid after preparative reverse phase HPLC. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamer δ 7.90 (s, 1H), 7.73 (s, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.68 (dd, J=12.0, 3.0 Hz, 1H), 5.63 (d, J=8.0 Hz, ½ H), 5.44 (d, J=8.0 Hz, ½ H), 4.85 (d, J=10.0 Hz, ½ H), 4.82 (d, J=10.0 Hz, ½ H), 4.03 (d, J=16.0 Hz, ½ H), 3.84 (m, 1½ H), 3.80 (s, 3H), 3.20 (m, 1H), 1.20 (m, 6H), 0.56 (d, J=6.5 Hz, 3/2 H), 0.38 (d, J=6.5H, 3/2 H). LC-MS (M+1): 604.3, 4.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(OCC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(Br)ccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A suspension of 4-bromo-2-(methyloxy)phenol (3.0 g, 14.78 mmol), potassium carbonate (2.99 g, 22.17 mmol) and 2-fluorobenzylbromide (1.78 ml, 14.78 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. Diethylether was added. The organic phase was then washed was washed with water and 1M NaOH, dried (Na2SO4), filtered and evaporated to afford the title compound (4.388 g, quant.). Rt (HPLC): 6.25 min; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (s, 1H), 7.0 (m, 2H), 5.1 (s, 2H), 3.7 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:18][CH2:17]3)=[C:11]([CH3:26])[CH:10]=2)=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:25])[CH2:23][CH2:24][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:20][CH2:21]3)=[C:11]([CH3:26])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C=CC(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CCN5CCOCC5)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)prop-2-en-1-one (41 mg, 0.88 mmol) and morpholine (0.1 mL) in DMF (1 mL) was stirred at rt overnight. The crude product was purified by RP-HPLC to give 1-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-3-morpholinopropan-1-one as a white powder; ESMS m/z 553.2 (M+H+).
Reaction SMILES: [H-].[Na+].F[C:4]1[C:5](/[C:17](/[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18]\[OH:19])=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[C:11]([OH:16])=[N:12][CH:13]=[N:14][CH:15]=1>C1COCC1.CN(C=O)C.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[C:5]3=[N:6][CH:7]=[CH:8][C:9]([C:10]4[C:11]([OH:16])=[N:12][CH:13]=[N:14][CH:15]=4)=[C:4]3[O:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: O/N=C(/c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Temperature: 70 °C
Yield: 49 %

Procedure:
To a suspension of sodium hydride (0.030 g, 0.742 mmol) in THF (Ratio: 1.8, Volume: 2.272 ml) was added dropwise (Z)-(3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone oxime (0.116 g, 0.353 mmol) in DMF (Ratio: 1.0, Volume: 1.262 ml) slowly. The reaction mixture was heated at 70° C. for 3.5 hr. Additional NaH (12 mg) was added. The reaction mixture was heated at 70° C. for 2.5 hr, and then allowed to cool to room temperature. The solvent was evaporated, and the mixture was further concentrated in vacuo to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-30% MeOH in CH2Cl2 over 25 min, tr=9 min) gave the title compound (53.4 mg, 0.173 mmol, 49.0% yield) as a yellow solid. ESI MS (M+H)+=309.1.