Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[C:26](/[CH:30]=[CH:31]/[S:32]([NH:35]C(=O)OC(C)(C)C)(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=2)=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][S:32]([NH2:35])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=2)=[N:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)/C=C/c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)CCc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.1 %

Procedure:
To a stirred solution of (E)-tert-butyl (2-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)vinyl)sulfonylcarbamate (100 mg, 0.171 mmol) in EtOAc (20 mL) was added 10% Pd/C (36.5 mg, 0.343 mmol) and the reaction mixture stirred for 12 h at RT under the H2 atmosphere using a bladder. The reaction mixture was filtered through a pad of CELITE® and the filtrate was treated with TFA (1 mL) then stirred at RT for 4 h. The volatile components were removed under reduced pressure. The resulting residue was dissolved in DCM (100 mL) and washed with 10% NaHCO3 (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-95 as described in general methods) to give 2-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethanesulfonamide (15.0 mg, 18.0%). LCMS Condition B-83: retention time 0.995 min, [M+1]=486.0, Purity: 96.17%. 1H NMR (400 MHz, CD3OD) δ ppm 3.24-3.30 (m, 2H), 3.42-3.52 (m, 2H), 4.90-4.93 (m, 2H), 6.77 (d, J=2.7 Hz, 1H), 7.30 (dd, J=7.0 Hz, J=5.3 Hz, 1H), 7.43-7.48 (m, 2H), 7.49-7.56 (m, 2H), 7.58-7.63 (m, 2H), 7.76 (d, J=2.7 Hz, 1H), 7.80 (td, J=7.7 Hz, J=1.8 Hz, 1H), 8.46 (d, J=4.2 Hz, 1H), 8.50-8.56 (m, 2H), 9.25 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C[N:19]([CH:21]=O)[CH3:20]>CC(CC(C)=O)C>[CH3:20][N:19]([CH2:21][CH2:4][C:3]1[CH:2]=[CH:10][C:9]([OH:11])=[CH:8][CH:7]=1)[C:4]([C:3]1[CH:7]=[C:8]([OH:13])[C:9]([O:11][CH3:12])=[CH:10][C:2]=1[Br:1])=[O:6]
Reactant: COc1cc(Br)c(C(=O)O)cc1O
Reactant: CN(C)C=O
Solvent: CC(=O)CC(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(Br)c(C(=O)N(C)CCc2ccc(O)cc2)cc1O
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 138 g 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13) in MIBK (690 mL) was added thionyl chloride (106 g) and DMF (13 mL) and the reaction mixture was heated to 80° C. and stirred at this temperature until TLC analysis indicated the complete disappearance of B13. The resulting mixture was subjected to distillation to remove the excess thionyl chloride. After distillation of thionyl chloride, the resulting acid chloride solution was cooled to room temperature and was added to a solution of 100 g of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr (A12 HBr) and 94 g Na2CO3 in 1000 mL of MIBK and 600 mL H2O pre-cooled to 0° C. A solution of NaOH (82.5 g) in 165 mL H2O was added slowly to maintain the temperature under 5° C. The reaction mixture was stirred at this temperature until TLC analysis showed the complete disappearance of B13 acid chloride. The pH of the reaction mixture was brought to 10-11 by adding more NaOH and the resulting mixture was heated to 50° C. and stirred at this temperature for another 1 h. The reaction mixture was cooled to room temperature and the aqueous layer was separated. The organic layer was concentrated to ⅕th of its volume. 500 mL of heptane was added. The precipitate was collected by filtration to give 163 g (65% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[CH3:30][C:31]([OH:35])([C:33]#[CH:34])[CH3:32].C(NC(C)C)(C)C.C(OCC)(=O)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCCCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([C:34]#[C:33][C:31]([OH:35])([CH3:32])[CH3:30])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(C#CC(C)(C)O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
0.5 g (0.997 mmol) of the compound obtained in example 107 in tetrahydrofuran (10 ml) was admixed under argon with 251 mg (2.992 mmol) of 2-methyl-3-butyn-2-ol, 0.419 ml (2.992 mmol) of diisopropylamine, 57 mg (0.299 mmol) of copper(I) iodide and 140 mg (0.199 mmol) of dichlorobis(triphenylphosphine)palladium(II). Subsequently, the mixture was stirred at RT overnight and then heated to reflux for 10 h. After cooling, the mixture was filtered. The filtrate was concentrated, slurried in acetonitrile, water and a small amount of dimethylformamide, and filtered once again. The filtrate thus obtained was admixed with ethyl acetate and cyclohexane and stirred briefly, the precipitated residue was filtered off, and the filtrate was concentrated and purified by means of preparative HPLC (acetonitrile: water+5% trifluoroacetic acid)−gradient. 110 mg of the title compound were obtained (23% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([OH:9])[C:5]=2[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc2c(O)noc2c1
Solvent: CC(=O)O
Product: Cc1cc2onc(O)c2cc1Br
Temperature: 80 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
A 25 ml high-pressure tube equipped with a stir bar and a screw-on Teflon cap was charged with 6-methyl-benzo[d]isoxazol-3-ol (745 mg, 5.0 mmole, 1.0 eq) and glacial acetic acid (5.0 ml). Neat Br2 (774 μL, 15.0 mmoles, 3.0 eq) was added dropwise. After stirring at 80° C. for 20 hours, the reaction was allowed to cool slowly to room temperature. The resulting precipitate was collected by filtration and washed quickly with 3×1.0 ml of glacial acetic acid. Crystallization of this crude product (624 mg) from 50 ml of MeCN yielded 567 mg of the title compound (96% purity determined RP-HPLC). Additional crystallization from 70 ml of toluene provided 519 mg (46%) as a white solid (98.1% purity determined by HPLC). (1H DMSO-d6, 400 MHz) δ 12.45 (s, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 2.45 (s, 3H); (13C CD3OD, 100 MHz) δ 165.96, 164.50, 142.34, 125.39, 119.73, 115.78, 112.67, 24.10.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]#[N:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([C:2]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=2)[C:24]#[N:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred mixture of 4-Chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (9.8 g, 45 mmol) and (3,5-Dichloro-phenyl)-acetonitrile (8.0 g, 43 mmol) in anhydrous DMF (70 ml) at 0° C. (ice bath) under nitrogen atmosphere, was portionwise added 60% sodium hydride (3.44 g, 86 mmol). After stirring for 1 hr., the mixture was further stirred at room temperature for overnight. The mixture was then neutralized with aqueous saturated ammonium chloride solution and the crude product was extracted with ethyl acetate and purified by silica gel column chromatography (eluent, EA:hexanes (1:9)) to afford 9.6 g (61%) of the title compound as a white solid. m.p. 135-136° C.; 1H NMR (200 MHz, CDCl3) δ 1.13 (3H, d, J=7.0 Hz), 1.18 (3H, d, J=7.0 Hz), 2.97 (1H, m), 3.99 (6H, s), 5.33 (1H, s), 7.25-7.33 (3H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][NH2:13].CO>C1COCC1>[F:1][C:2]1[C:3]([C:9]([NH:13][CH3:12])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN
Reactant: O=C(O)c1ncc(F)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ncc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (600 mg) was added to a solution of 3,5-difluoropyridine-2-carboxylic acid (500 mg) in THF (10 ml), followed by stirring at 50° C. for one hour. The reaction solution was returned to room temperature, a 40% methylamine/methanol solution (1 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100 linear gradient) to obtain 3,5-difluoro-N-methylpyridine-2-carboxamide (293 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:32])[F:33])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: Cc1nc(CC(=O)N2CCN(c3ccc(OC(F)F)c(OC4CCC4)c3)C[C@@H]2Cc2ccccc2)n[nH]1

Procedure:
Prepared by the method outlined for Example 189 using (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid and (S)3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine (Example 4, Compound 92) as starting materials. Product as an oil. LC/MS (Method B) 2.66 min, [M+1]+ 512. Potency class A.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[PH:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C(=O)([O-])N.[O-]S(C(F)(F)F)(=O)=O>>[NH:1]1[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6]1.[PH:7](=[O:14])([O:11][CH2:12][C:13]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:8][CH2:9][C:10]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO[PH](=O)OCC
Agent: C1=CNCCC1
Agent: NC(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Yield: 59 %

Procedure:
The tetrahydropyridine-dibenzyl phosphonate 13: The compound 13 was obtained by the same procedure as described for compound 11 using the pyridine 9 (10.0 mg, 0.018 mmol) and the triflate 12 (9.4 mg, 0.022 mmol). The product 13 was purified by preparative TLC to afford the dibenzyl phosphonate 13 (8.8 mg, 59%): 1H NMR (CDCl3) δ 7.73 (d, 2H, J=8.7 Hz), 7.35 (s, 10H), 7.00 (d, 2H, J=8.7 Hz), 5.65 (d, 1H2H, J=5.1 Hz), 5.39 (br, 1H), 5.15-4.92 (m, 6H), 4.03-3.77 (m, 6H), 3.77-3.62 (m, 2H), 3.56 (br, 1H), 3.24-2.62 (m, 9H), 2.32 (d, 1H, J=13.5 Hz), 2.24-1.75 (m, 6H), 0.94 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.3 Hz); 31P NMR (CDCl3) δ 25.5; MS (ESI) 842 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[NH:15][C:16](=O)[C:17]4[CH:22]=[CH:21][NH:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Br)(Br)([Br:26])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Br:26][C:16]1[C:17]2[CH:22]=[CH:21][NH:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=1
Reactant: O=c1[nH]c(Nc2ccc(N3CCOCC3)cc2)nc2[nH]ccc12
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1nc(Nc2ccc(N3CCOCC3)cc2)nc2[nH]ccc12
Temperature: 25 °C

Procedure:
A mixture of 2-[(4-morpholin-4-ylphenyl)amino]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one A (312 mg, 1 mmol), phosphorous oxybromide (717 mg, 2.5 mmol), and diisopropylethylamine (130 mg, 1 mmol) in anhydrous toluene (15 ml) was heated at reflux under N2 overnight. The mixture was cooled down to room temperature, and the solid was filtered, washed with sat. NaHCO3, water, and dried over MgSO4. The solvent was removed in vacuo to give the product 4-bromo-N-(4-morpholin-4-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine B (284 mg, 76%) as a black solid. This was clean and used as such without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)[CH:11]=[CH:10][CH:9]=[CH:8]1.[NH2:21][C:22]1[CH:34]=[C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:35]([C:33]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[C:22]([NH:21][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([N:7]3[CH:8]=[CH:9][CH:10]=[CH:11]3)[CH:13]=2)[CH:34]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)c1cccc(-n2cccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.015 mL of N,N-dimethylformamide was added to a mixed solution of 2.0 mL of methylene chloride and 0.024 mL of oxalyl chloride containing 47 mg of 3-(1H-pyrrol-1-yl)benzoic acid and stirred at room temperature for 30 minutes, 71 mg of tert-butyl 2-amino-4-phenoxybenzoate and 0.090 mL of triethylamine were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=40:1] to obtain 31 mg of tert-butyl 4-phenoxy-2-(3-(1H-pyrrol-1-yl)benzamido)benzoate as white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].O1CCOCC1>C1COCC1>[CH3:11][N:12]([CH3:13])[C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:8]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CNC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C)C)c(C)o1
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonylchloride (2.19 g; 13.8 mmol) in 10 ml of THF was added to a 2M solution of dimethylamine in dioxane (21 ml; 42 mmol) in 80 ml of THF at rt. After stirring for 1 hr, the volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with saturated potassium bisulfate solution (100 ml), 1N NaOH (50 ml) and brine (50 ml). Drying over MgSO4 and concentration in vacuo afforded compound 866A (1.84 g, 80%) as an amber liquid. 1HNMR (CDCl3): δ 2.23 (s, 3H), 2.33 (s, 3H), 3.04 (s, 6H), 5.96 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:12]([O-])=O>CO>[NH2:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][CH:2]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Solvent: CO
Product: CCOC(=O)c1cc(N)cs1

Procedure:
A solution of ethyl 5-bromo-4-nitrothiophene-2-carboxylate (Int. 40) (500 mg, 1.785 mmol) in MeOH (35 ml) was hydrogenated in a continuous-flow hydrogenation reactor (H-Cube apparatus) (flow rate: 1.0 ml/min, Temp: 50° C., H2 pressure: 20 bar). The solvent was evaporated affording ethyl 4-aminothiophene-2-carboxylate (Int. 41) which was used without any additional purification (350 mg, MS/ESI+172.1 [MH]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:2]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1c[nH]c2ccccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 16.1 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 5.0 g of 2-(indol-3-yl)-ethanol, 14.4 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 7.73 ml of tributylphosphine, 7.83 g of 1,1'-(azodicarbonyl)dipiperidine and 150 ml of anhydrous benzene were used, to give 3.03 g of the title compound, melting at 81.0-82.5° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:62]=[CH:61][C:47]3[N:48]([CH3:60])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([Br:58])=[C:54]([F:59])[CH:53]=4)=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:49]2[N:48]([CH3:60])[C:47]3[CH:61]=[CH:62][C:44]([O:43][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:45][C:46]=3[N:50]=2)=[CH:53][C:54]=1[F:59]
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Cn1c(Nc2ccc(Br)c(F)c2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Agent: NC(N)=S
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Product: Cn1c(Nc2ccc(Br)c(F)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-fluorobenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-fluorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-fluorophenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=456.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].ClCCN1CCCC1>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:12][CH2:13][N:8]3[CH2:1][CH2:11][CH2:10][CH2:9]3)[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: ClCCN1CCCC1
Product: CC1N(CCN2CCCC2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and 1-(2-chloroethyl)pyrrolidine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:19])([F:18])[C:9]([CH3:17])([CH3:16])[C:10](N(OC)C)=[O:11]>CCOCC>[F:7][C:8]([F:19])([F:18])[C:9]([CH3:17])([CH3:16])[CH:10]=[O:11]
Reactant: CON(C)C(=O)C(C)(C)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a 250-mL of three neck round-bottomed flask equipped with goose neck for nitrogen and for thermocouple was added lithium aluminium hydride, 1 M solution in Et2O (25.3 ml, 25.3 mmol) at 0° C. To the cooled mixture was added a solution of 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (A294-1) (5.0325 g, 25.3 mmol) in Et2O (47.7 ml) dropwise over 35 min at 0° C. After the completion of the addition, the reaction mixture was further stirred at 0° C. After 2 h, the mixture was carefully quenched at 0° C. with water (0.96 mL), NaOH (15%, 0.96 mL) and water (2.88 mL) and the mixture was vigorously stirred for 40 min. The reaction mixture was diluted with Et2O (50 mL), treated with Na2SO4 and then filtered through a Celite pad, washed with Et2O (100 mL). The filtrate was concentrated in vacuo to provide 3,3,3-trifluoro-2,2-dimethylpropanal (A294-2) (3.2304 g, 23.06 mmol, 91% yield) as yellow liquid. 1H NMR (400 MHz, CDCl3) δ 9.69 (1H, d, J=1.4 Hz), 1.31 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
The 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.24 mmol) and piperazine-1-carboxylic acid tert-butyl ester (603 mg, 3.24 mmol) were dissolved in 11.0 mL of NMP then treated with diisopropylethyl amine (845 μL, 4.85 mmol). The yellow solution was heated to 80 C overnight to completion and was allowed to cool to room temperature. The solution was diluted with ethyl acetate, poured into diluted NaHCO3 solution, and extracted with ethyl acetate. The combined organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude material as a tan solid. The material was triturated with DCM/hexanes to afford the 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a cream-colored solid (824 mg, 84%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.06 (s, 1H), 4.05 (m, 4H), 3.67 (m, 4H). LCMS (APCI+) m/z 305 [M+H]+; Rt=2.14 min.