Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([N:33]([C:41]4[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][N:42]=4)C(=O)OC(C)(C)C)[CH:21]=[C:22]([NH:24][C:25](=[O:32])[NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:23]=3)=[CH:16][N:17]=2)[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[CH:27]1([NH:26][C:25]([NH:24][C:22]2[CH:21]=[C:20]([NH:33][C:41]3[N:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][N:42]=3)[CH:19]=[C:18]([C:15]3[S:14][C:13]([C:9]4([OH:8])[CH2:10][CH2:11][CH2:12]4)=[N:17][CH:16]=3)[CH:23]=2)=[O:32])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N(c1cc(NC(=O)NC2CCCC2)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC3)s2)c1)NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a solution of the product of Step 3 (56 mg, 0.076 mmol) in dichloromethane (1 mL) was added TFA (1 mL) and the mixture was stirred for 60 minutes at room temperature. The mixture was concentrated in vacuo, then the residue was diluted with ethyl acetate (30 mL) and washed with sat. NaHCO3(aq) (30 mL) and brine (30 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in THF (1 mL), TBAF (228 μL, 1.0 M; 0.228 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, and the residue purified by chromatography on silica gel (100:0 to 80:20, ethyl acetate: EtOH) provided 9 mg (0.017 mmol, 28%) of the desired 1-cyclopentyl-3-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)urea as a white solid. MS APCI: [M+H]+ m/z 519.1. 1H NMR (400 MHz, d6-acetone): δ 9.22 (s, 1H); 8.81 (d, J=4.9 Hz, 1H); 8.00-7.90 (m, 3H); 7.78 (s, 1H); 7.66 (s, 1H); 7.23 (d, J=4.9 Hz, 1H); 5.90 (d, J=7.0 Hz, 1H); 5.49 (s, 1H); 4.17-4.08 (m, 1H); 2.79-2.59 (m, 2H); 2.49-2.37 (m, 2H); 2.06-1.88 (m, 4H); 1.82-1.48 (m, 4H); 1.51-1.42 (m, 2H). rhSYK activity=+++
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[C:11](=[O:21])[N:10]2[C:22]([CH2:31][C:32](OC)=[O:33])([CH2:26][C:27](OC)=[O:28])[NH:23][C:24](=[O:25])[C:9]=12>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[C:11](=[O:21])[N:10]2[C:22]([CH2:26][CH2:27][OH:28])([CH2:31][CH2:32][OH:33])[NH:23][C:24](=[O:25])[C:9]=12
Reactant: COC(=O)CC1(CC(=O)OC)NC(=O)c2c(Cl)cc(Nc3ccncn3)c(=O)n21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(CCO)(CCO)n2c1c(Cl)cc(Nc1ccncn1)c2=O

Procedure:
To a slurry of lithium aluminum hydride (71 mg, 1.9 mmol) in tetrahydrofuran (3 mL) at 0° C. a solution of dimethyl 2,2′-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)diacetate (5, 280 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added slowly. After consumption of starting material the reaction mixture was quenched with 10% sodium hydroxide solution (1 mL), diluted with 10 ml of ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduce pressure to afford the residue. The residue was purified prep HPLC to afford 8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 153) as yellow solid. Yield: 0.047 g, 19%; MS (ESI) m/z 366.09 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.58-9.57 (brs, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.44-7.42 (d, J=5.6 Hz, 1H), 4.44 (brs, 2H), 3.34-3.26 (m, 4H), 2.79-3.73 (m, 2H), 2.11-2.08 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=3)[C:12]([CH2:22][CH3:23])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[C:25]1([NH:24][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([C:12]([CH2:22][CH3:23])=[N:11][N:10]3[CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:21])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
46 μL (0.629 mmol, 1.3 equiv) thionyl chloride were added to room temperature solution of 125 mg (0.484 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 5 μL DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 h, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. The crude acid chloride was dissolved in 5 mL CH2Cl2 and added to a room temperature solution of 49 μL (0.532 mmol, 1.1 equiv) aniline and 67 μL (0.484 mmol, 1.0 equiv) triethylamine in 5 mL CH2Cl2. After 18 h at room temperature, the reaction mixture was diluted with 75 mL ethyl acetate, washed 1×15 mL each 1N HCl, H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 180 mg of an amber oil, which was purified on a silica gel column to give 160 mg of an off-white solid. Crystallization from ethyl acetate/hexanes gave 130 mg (81%) of a white crystalline solid: mp 146-147° C.; Anal. calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.65; H, 7.03; N, 12.55.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:14]([CH2:12][CH3:13])[CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:18])([F:20])[F:19])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1Cl

Procedure:
Prepared similarly to Example 56 from 2-chloro-6-methylbenzoylchloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol. Purification by mass directed autopreparation (System B) resulted in separation of atropisomers of the title compound:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCSc1cccc2nccn12)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 mmoles) and triethylamine (0.80 ml, 5.74 mmoles) in methylene chloride (25 ml) was added benzoyl chloride (1.10 ml, 11.6 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.32 g of the desired product (88.1%, white solid).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH3:8].O.C([OH:14])C.Cl>C(OC(=O)C)(=O)C>[Br:1][C:2]1[C:3]([CH2:10][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc[n+]([O-])c(C)c1Br
Reactant: CCO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1ccnc(CO)c1Br

Procedure:
3-Bromo-2,4-dimethylpyridine-N-oxide (14.7 g) in warm acetic anhydride (150 ml) was added dropwise to acetic anhydride (500 ml) at 125° and the mixture was refluxed for 1/2 hour, allowed to cool and then poured into water/ethanol (4:1, 500 ml). The solution was acidified with dilute hydrochloric acid and evaporated to dryness. The residue was refluxed with 2 N hydrochloric acid (100 ml) for 1 hour, cooled and extracted with chloroform. The aqueous phase was adjusted to pH 12 with sodium hydroxide and was extracted with chloroform, and this chloroform extract was evaporated to a residue which was crystallised from n-hexane to give 3-bromo-2-hydroxymethyl-4-methylpyridine (5.8 g) m.p. 75°-77°.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.CCCCCC>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Cl:21][C:15]1[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:3][CH2:1][CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[C:19]([CH3:20])[CH:18]=[CH:17][N:16]=1
Reactant: CCN
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNc1ncccc1C(=O)Nc1c(C)ccnc1Cl
Temperature: 165 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Ethylamine (12.7 g) was added to a suspension of 21.0 g of the 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide in 150 ml of xylene in a steel bomb. The mixture was then heated in an oil bath to 165° C. for 6 hrs. and then stirred overnight at room temperature. The solvent was removed in vacuo and water added to the residue. The product was extracted with ether, dried (sodium sulfate) and concentrated to give an oil. This was dissolved in ethyl acetate followed by hexane at which time a precipitate formed. The solid was filtered and dried to give 16.5 g of the title compound, m.p. 122°-124° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>CC#N>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)=[O:24]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1ccsc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OCC(Cl)(Cl)Cl)CC1c1ccsc1
Yield: 84.2 %

Procedure:
A solution of 1.02 g (3.38 mmol) of 1-benzyl-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine (Example 1) and 0.51 mL (3.72 mmol) of 2,2,2-trichloroethyl chloroformate in 15 mL of CH3CN was stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was purified by chomatography (silica, hexanes, ethyl acetate, 6:1) to give 1.1 g of the title compound. 1H NMR (CDCl3) δ3.21 (m, 1H), 3.58 (m, 1H), 3.716, 3.723 (s, 3H), 4.81 (m, 2H), 7.00 (m, 1H), 7.12 (s, 1H), 7.33 (m, 1H);
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH2:13])[CH3:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:36]3[N:37]=[C:38]4[C:44]([C:45](O)=[O:46])=[CH:43][N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:39]4=[N:40][CH:41]=3)=[N:31][N:32]2[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:15][C:4]([F:14])([F:3])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH:13][C:45]([C:44]2[C:38]3[C:39](=[N:40][CH:41]=[C:36]([C:30]4[C:29]5[C:33](=[CH:34][C:26]([F:25])=[CH:27][CH:28]=5)[N:32]([CH3:35])[N:31]=4)[N:37]=3)[N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=2)=[O:46])[CH3:12])[CH:6]=1
Reactant: C[C@@H](N)c1cc(C(F)(F)F)ccn1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of (R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethylamine dihydrochloride (89 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 122 mg (88%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH2:23]>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:23][C:19]2[S:18][CH:22]=[CH:21][N:20]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncccc1=O
Yield: 29 %

Procedure:
Using the method described in Example 78, Step 3,3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (prepared as in Example 78, Step 2) and thiazol-2-ylamine afforded 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide as a white solid (39.9 mg, 29%); ES+-HRMS m/e calcd for C15H18N4O2S [M+H+] 319.1223 found 319.1223. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.75 (m, 9H), 1.99 (m, 1H, CH), 2.28 (m, 1H), 5.60 (dd, J=4.5, J=10.3 Hz, 1H), 6.98 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.45 (dd, Jo=9.4, Jo=3.6 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 8.02 (dd, Jo=3.6 Hz, Jm=1.5 Hz, 1H), 12.58 (s, 1H).
Reaction SMILES: [N+:1](=[C:3]([C:10](=[O:13])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].C(N(CC)CC)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:33]Br>C(Cl)Cl>[N+:1](=[C:3]([C:10](=[O:13])[CH:11]([Br:33])[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2]
Reactant: BrBr
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C(C)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-cooled solution of allyl 2-diazo-3-ketopentanoate (9.1 g, 0.05 mole) in 100 mL of CH2CL2, was added 8.35 mL of triethylamine, followed by dropwise addition of 11.6 mL trimethylsilyl triflate (13.34 g, 0.06 mole) over twenty minutes. The resulting solution (orange) was stirred at 0° C. for one hour. A solution of bromine (8.0 g, 0.05 mole) in 30 mL CH2Cl2 was added over twenty minutes at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was then washed with water three times, dried over magnesium sulphate and concentrated to give the title compound as an oil (12.74 G, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.Cl[Sn]Cl.[C:21]([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:21]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1
Reactant: O=C([O-])[O-]
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Product: CN1CCC[C@H]1COc1cc(N)ccc1Cl
Reaction time: 0.67 h

Procedure:
(S)-2-(2-Chloro-5-nitro-phenoxymethyl)-pyrrolidine (3.42 g, 12.63 mmol) and SnCl2 (7.19 g, 37.9 mmol) in 45 mL EtOH were heated at 75° C. for 11 h. The reaction was treated with about 15 mL 1 N K2CO3 (aq) and stirred 40 min. The suspension was filtered through Celite and concentrated down to aqueous, which was then diluted with EtOAc and 1 N NaOH (aq). The layers were separated, and the organic layer was washed twice with 1 N NaOH and once with mix of brine and 1 N NaOH. The aqueous layers were extracted twice with fresh EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated down to dryness to yield the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:19]=2[NH2:20])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:18]=1[N:15]1[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1)=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1cc(Br)ccc1O
Yield: 65.9 %

Procedure:
Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH2:5][C:6]([O:14][CH3:15])([CH:11]=[CH:12][CH:13]=1)[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH2:5][C:6]([O:14][CH3:15])([CH:11]=[CH:12][CH:13]=1)[CH:7]=[O:8]
Reactant: COC(=O)C1=CC=CC(OC)(C(=O)OC)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=CC=CC(C=O)(OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a -78° to -100° solution of 1.0 mol of 3-methoxyisophthalic acid dimethyl ester in 1-10 l of toluene is slowly added 1.0 mol of diisobutylaluminum hydride as a 1 M solution in n-hexane. The reaction is stirred for 3 hours after the addition and then quenched by the addition of 10 mol of anhydrous methanol. The reaction is allowed to warm to room temperature and stirred until a filterable precipitate forms. The reaction is filtered and the filtrate evaporated to a residue. The residue is purified by crystallization, distillation or chromatography to yield 3-methoxyisophthalaldehydic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:12]=2)=[CH:6][N:5]=1.[Cl-].[Ca+2].[Cl-].O.C(O)C>[Fe].C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:12]=2)=[CH:8][CH:9]=1
Reactant: COCc1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: COCc1ccc(Oc2ccc(N)c(OC3CCOCC3)c2)cn1
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 2-(methoxymethyl)-5-[4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]pyridine (680 mg), iron powder (530 mg), calcium chloride (20 mg), water (3 mL), and ethanol (15 mL) was heated under reflux for 3 hr. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4, volume ratio) to give the title compound (480 mg, yield 76%) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.Cl.[CH:22]([N:25]([CH2:29][CH2:30]Cl)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+].O>CN(C)C=O>[CH3:23][CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][CH2:30][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[CH3:24]
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1)C(C)C
Reaction time: 48 h

Procedure:
A 2.64 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 60 ml of dimethylformamide by warming on a steam bath and then cooled. A 2.0 g portion of diisopropylaminoethyl chloride hydrochloride was added and dissolved with stirring. A 20 ml portion of 5N sodium hydroxide was added dropwise over 5 minutes, then 5 ml of water was added and the mixture was stirred for 20hours. The mixture was then heated on a steam bath for 30 minutes, allowed to stand 48 hours and then evaporated. The residual gum was purified by flash dry column chromatography on silica gel eluting fractions 1-3 with methanol and fractions 4-6 with 1% methanol in chloroform. Fractions 4-6 were combined and evaporated, giving 500 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cc(F)cc(F)c2)cc1
Yield: 54.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3,5-difluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 3,5-difluorophenylboronic acid (0.038 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.053 g (55%) of the title compound as a white solid.