Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.O>CN(C=O)C>[C:1]1([N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 17.0 g (88.1 mmol) of tert-butyl phenylcarbamate in 150 ml of hexanes 35.2 ml (88.1 mmol) of 2.5 M nBuLi in hexanes was slowly added at gentle reflux for ca. 15 min. This mixture was stirred for additional 30 minutes and then evaporated to dryness. The resulting white powder was added to a solution of 30.6 g (88.1 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 300 ml of DMF. This mixture was stirred for 20 minutes at 75° C. and then poured into 1200 cm3 of cold water. The product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed by 2×300 ml of water, dried over MgSO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol. then 10:1, vol.). Yield 28.0 g (69%) of yellowish oil. Anal. calc. for C28H34BNO4: C, 73.21; H, 7.46; N, 3.05. Found: C, 73.12; H, 7.62; N, 3.24. 1H NMR (CDCl3): 8.19 (m, 1H, 8-H in naphthyl), 7.85 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.77 (m, 1H, 5-H in naphthyl), 7.60 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.40 (m, 1H, 6-H in naphthyl), 7.20 (m, 2H, 3,5-H in Ph), 7.13 (m,\2H, 2,6-H in Ph), 7.08 (m, 1H, 4-H in Ph), 5.21 (s, 2H, CH2N), 1.42 (s, 9H, tBu), 1.38 (s, 12H, CMe2CMe2).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccncc2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 19, using 1.00 g (4.62 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and isonicotinic acid instead of cyclopentylacetic acid to obtain 1.16 g of 1-benzyl-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[Cl:31]CCl>CO.Cl.CCOCC>[ClH:31].[CH3:25][N:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(-c2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (2.00 g, 4.93 mmol) in dichloromethane (2 mL) and methanol (1 mL), 2M HCl in Et2O (25 mL) was added and the resulting mixture was stirred overnight at room temperature.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C(N(CC)CC)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(CCl)c1)N1CCCCC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
3-Chloromethylbenzoyl chloride (1.45 ml) was added to a solution of piperidine (1 ml) in triethylamine (2 ml) and the mixture was stirred under nitrogen at 5° C. for 45 min. Water was added, the product was extracted with dichloromethane and the extract was washed with water, dried over sodium sulphate and evaporated to give 1(3-chloromethylbenzoyl)piperidine (2.32 g) as an oil.
Reaction SMILES: [C:1]1([CH3:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[CH3:8][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: Cc1ccccc1S
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: Cc1ccccc1Sc1cc(C(=O)O)co1
Temperature: 175 °C

Procedure:
In an open flask cuprous oxide (2.25 g., 15.7 mmoles) and o-toluenethiol (3.89 g., 31.4 mmoles) were combined in 40 ml. of dimethylformamide and heated in a 150° C. oil bath until a thick yellow mixture formed. The mixture was cooled slightly and 5-bromofuran-3-carboxylic acid [3.0 g., 15.7 mmoles; Gilman and Burtner, J. Am. Chem. Soc. 55, 2903 (1933)] in 40 ml. of dimethylformamide added. The mixture was heated in a 175° C. oil bath for approximately 16 hours. The reaction mixture was cooled, solids removed by filtration, the filtrate diluted with 500 ml. of water, acidified with 6 N hydrochloric acid and product extracted into three portions of ethyl acetate. The ethyl acetate extracts were combined, evaporated to an oil, the oil taken up in 1 N sodium hydroxide, the basic solution washed with ether, cooled, reacidified and product (650 mg.) recovered by filtration. Recrystallization from methanol/water gave purified 5-(2-methylphenylthio)furan-3-carboxylic acid (485 mg., m.p. 148°-150° C., m/e 234).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1Br
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccnc1C=O
Temperature: 90 °C
Yield: 63.2 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (128 mg, 0.69 mmol) and 2-methoxybenzeneboronic acid (111 mg, 0.73 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (41 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. overnight. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (EtOAc/Hexanes, 80:20, then 70:30) gave 3-(2-methoxy-phenyl)-pyridine-2-carbaldehyde (93 mg, 63%) as a yellow solid. 1H NMR (CDCl3) δ 3.74 (s, 3H), 6.99 (d, 1H, J=8.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.25 (dd, 1H, J=7.4, 1.7 Hz), 7.40-7.49 (m, 1H), 7.55 (dd, 1H, J=7.9, 4.8 Hz), 7.74 (dd, 1H, J=7.9, 1.8 Hz), 8.80 (dd, 1H, J=4.6, 1.5 Hz), 9.95 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])=[CH:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(C2C(=O)Nc3cc(Cl)ccc32)=CN1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)=CN1
Temperature: 60 °C

Procedure:
A mixture of 5-[6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (1.4 g, 4.00 mmol) (from Example 20a supra), 3-chlorobenzyl bromide (0.97 g, 4.67 mmol) (Aldrich), potassium iodide (0.79 g, 4.73 mmol) and potassium carbonate (1.2 g, 8.60 mmol) in acetone (30 mL) was heated at 60° C. for 12 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 1:9, V/V) to give rac-5-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester as a brown solid. (Yield 1.5 g, 79%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13](I)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([O:34][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:30]4[CH:42]=[CH:41][C:33]([O:34][C:35]5[N:36]=[CH:37][CH:38]=[CH:39][N:40]=5)=[CH:32][CH:31]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Reactant: CC1(C)OB(c2ccc(Oc3ncccn3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 75.7 %

Procedure:
A mixture of 1-(1,4-dioxaspiro[4,5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate N) (1.50 g, 0.00374 mol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-pyrimidine (intermediate BA) (1.23 g, 0.00412 mol), tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.00022 mol) and sodium carbonate (0.993 g, 0.00937 mol) in 40 mL 1,2-dimethoxyethane and 20 mL water was heated at 80° C. for eighteen hours, after which time additional 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.15 g, 0.00037 mol) was added. The mixture was stirred for an additional hour and then allowed to cool to ambient temperature. The precipitate was filtered and washed with 1,2-dimethoxyethane and dried in vacuo, to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.26 g, 0.00283 mol): 1H NMR (DMSO-d6, 400 MHz) 8.68 (d, 2H), 8.254 (s, 1H), 7.73 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 4.78-4.84 (m, 1H), 3.91 (s, 4H), 2.22-2.30 (m, 2H), 1.73-1.92 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:18][O:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1O
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 4-hydroxy-2-(4-pyridyl)-thiazole-5-carboxylate (0.5 gm, 2.0 mmol) in 30% methanol in benzene (30 mL) was added (trimethylsilyl)diazomethane (2.0M solution in hexanes) (1.0 mL, 2.0 mmol). After stirring for 30 minutes at room temperature, an additional 1.0 mL of (trimethylsilyl)diazomethane was added. The mixture was stirred overnight at room temperature and evaporated. The title compound was purified by flash chromatography eluting with 20% acetone in hexane; yield 206 mg.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH:17][C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:23][CH2:24][CH:20]([OH:21])[C:18]2=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C2CCCO2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(O)C2=O)c1I)OC(C)=O

Procedure:
To a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-5-[[(tetrahydro-2-furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (0.25 g, 0.26 mmol) (the title compound of Example 19) in dry CH2Cl2 (5 mL) was added triethyl amine (0.01 mL). The solution was cooled to 0°-5°, and to this was added dropwise a solution of dimethylboron bromide in CH2Cl2 (0.12 g, 0.5 mL/2 mMol solution in CH2CL2). After stirring the mixture at 0°-5° for 6-8 hours, the mixture was added to a vigorously stirred solution of aqueous saturated sodium bicarbonate (5 mL). After stirring for 5 minutes, ethyl acetate (50 mL) and water (10 mL) were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the omega-bromo-alpha-hydroxypentanoyl anilide as an off-white fluffy solid (260 mg).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3R)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (124 mg, 0.25 mmol), triethylamine (0.087 ml, 0.63 mmol), L-lactic acid (27.2 mg, 0.30 mmol), and 1-hydroxybenzotriazole (42.6 mg, 0.28 mmol), the resulting mixture was stirred at room temperature for 17 hours followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol), and the resulting mixture was stirred at 40° C. for 8 hours. The resulting mixture was partitioned with ethyl acetate and water and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=90:10) to give the title compound (38.9 mg) as a pale yellow solid.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[CH3:8][N:9]([CH3:29])[CH2:10][CH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[C:21]([C:24]1[S:28][CH:27]=[N:26][CH:25]=1)(O)[CH3:22]>C(#N)C.ClCCl>[CH3:29][N:9]([CH3:8])[CH2:10][CH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[CH:21]([C:24]1[S:28][CH:27]=[N:26][CH:25]=1)[CH3:22]
Reactant: CN(C)CCc1sc2ccccc2c1C(C)(O)c1cncs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(c1cncs1)c1c(CCN(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of NaI (24 mg, 0.16 mmol)) and TMSCl (20 uL, 0.16 mmol) in acetonitrile (0.5 mL) was stirred for 15 min at room temperature. A solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-thiazol-5-yl-ethanol (Compound 17-1) (3 mg, 0.01 mmol) in dichloromethane (1.3 mL) was added and the reaction was stirred in a sealed vial at 100° C. for 3 hrs. The mixture was quenched with 1M Na2S2O3 until colorless and diluted NH4OH was added until pH ˜8. The product was extracted with EtOAc and the combined organic layers were washed with diluted NH4OH, concentrated and subjected to mass triggered preparative HPLC purification to afford dimethyl-{2-[3-(1-thiazol-5-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 17-2). MH+=317.0, tR=4.24 min, (Method 2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])(=[O:27])=[O:26]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:31])=[O:30])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (54 mg) in DCM (2 ml) and triethylamine (44 ul) was added methylsulfonylmethylsulfonyl chloride (45 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature overnight. Aqueous work-up and purification on silica gave 2-chloro-6-(4-methanesulfonylmethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (35 mg).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CN(C=O)C.[OH-].[Na+]>O>[C:18]([CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CSc1ccc(C(=O)c2ccccc2)cc1
Temperature: 107.5 °C
Yield: 75.2 %

Procedure:
55 g 4-chloro benzophenone and 24 g mercaptoacetic acid are added into a 500 ml three-neck flask, and are dissolved with 350 ml DMF to obtain a solution, and then 23 g solid sodium hydroxide is added into the solution. Heating the solution to reflux (105-110° C.), and starting to cool the solution when the content of 4-chloro benzophenone detected by HPLC is less than 1%. The reaction solution is added into 500 ml water, and then water insoluble substances are extracted with 100 ml methylbenzene. Concentrated hydrochloric acid is used to regulate the pH value of the aqueous phase to 3-4, then some solid substances precipitates, filtering to obtain crude products, and the weight after drying is 58 g; the dried crude products are recrystallized in dichloroethane to obtain 52 g white crystal, with a yield of 75% and a melting point of 130-132° C. 1H-NMR data (solvent DMSO-d6): δ3.796 ppm, s, 2H; δ7.402, 7.429 ppm, d, 2H, δ7.451, 7.476, 7.501 ppm, t, 2H, δ7.567, 7.590, 7.614 ppm, t, 1H, δ7.740, 7.767 ppm, d, 2H, δ7.753, 7.775 ppm, d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([C:22]3[CH:21]=[C:20]4[C:25]([C:16]([NH:15][C:4]5[CH:5]=[CH:6][C:7]([S:8][C:9]6[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=6)=[C:2]([Cl:1])[CH:3]=5)=[C:17]([C:29]#[N:30])[CH:18]=[N:19]4)=[CH:24][C:23]=3[O:26][CH3:27])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCCC2)CC1
Temperature: 105 °C
Yield: 65.6 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 290mg (1.72 mmol) of 4-piperidinopiperidine in 1.5 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 94:6 methylene chloride/methanol to 89:10:1 methylene chloride/methanol/ammonium hydroxide) gives 193 mg of 7-(1,4′-bipiperidin-1′-yl)-4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxyquinoline-3-carbonitrile as a beige solid, mp 221-223° 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.[NH:20]1[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]1>>[O:26]=[S:23]1(=[O:27])[CH2:24][CH2:25][N:20]([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)[CH2:21][CH2:22]1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: O=S1(=O)CCNCC1
Product: COc1ccc(Nc2nc3c(N4CCS(=O)(=O)CC4)cccn3n2)cc1

Procedure:
8-(1,1-dioxidothiomorpholin-4-yl)-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine 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 thiomorpholine 1,1-dioxide (25.0 mg, 0.185 mmol) in a manner analogous to Example 30. Product isolated as a tan solid (0.052 g, 89%). MP=231-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.4, 1.1 Hz, 1H), 7.50-7.45 (m, 2H), 6.94-6.89 (m, 2H), 6.77 (dd, J=7.7, 6.7 Hz, 1H), 6.73 (dd, J=7.6, 0.9 Hz, 1H), 6.57 (s, 1H), 4.12-4.06 (m, 4H), 3.81 (s, 3H), 3.28-3.23 (m, 4H). MS=374 (MH)+.