Azzindani/Open_Reaction_Data huggingface dataset:
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: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
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: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[OH:13][C:14]([CH2:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:18]=1)=[O:15].[ClH:29].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:29].[OH:15][C:14]([CH2:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:18]=1)=[O:13]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(N)O
Reaction time: 2 h

Procedure:
The Boc-aminopropanol-felbinac obtained above (1.69 mmol) was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (3 ml) was added thereto under ice-cooling. The mixture was returned to room temperature, followed by stirring for 2 hours. After confirming disappearance of Boc-aminopropanol-felbinac by TLC, diethyl ether was added thereto and the thus formed precipitate was centrifuged. The thus obtained precipitate was subjected to three times of decantation with diethyl ether and then dried under reduced pressure to give the titled compound (511.7 mg, yield 99%). The structure was identified by 1H-NMR (CDCl3:CD3OD=1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:46])[C@@H:23]([NH:25][C:26]([C@@H:28]([N:30]([CH3:45])[C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38](OC(C)(C)C)=[O:39])=[O:32])[CH3:29])=[O:27])[CH3:24])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl>ClCCl>[CH3:24][C@@H:23]1[NH:25][C:26](=[O:27])[C@H:28]([CH3:29])[N:30]([CH3:45])[C:31](=[O:32])[C@H:33]2[N:34]([CH2:35][CH2:36][CH2:37]2)[C:38](=[O:39])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:14][C:15](=[O:16])[C@H:17]2[N:18]([CH2:19][CH2:20][CH2:21]2)[C:22]1=[O:46]
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)OCc2ccccc2)COC(=O)[C@@H]2CCCN2C1=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
109.0 g (158 mmol) of the carboxylic acid from example 9A and 116.4 g (632 mmol) of pentafluorophenol are dissolved in 1000 ml of anhydrous dichloromethane, cooled to −20° C. and 39.4 g (205 mmol) of EDC are introduced. The reaction mixture is stirred overnight with slow warming to RT. The solvent is removed in vacuo and the residue is treated with hydrogen chloride in dioxane (600 ml) with ice cooling. The mixture is stirred at RT for 3 h, the solvent is removed in vacuo and the residue is taken up three times using toluene and again concentrated to dryness. The residue is divided into thirds and each part is treated as follows: The intermediate product is taken up in dichloromethane (900 ml) and introduced with a flow rate of 0.8 ml/min at RT into a vigorously stirred 2-phase mixture of 1.5 l of aqueous sodium hydrogencarbonate solution and 5 l of dichloromethane and stirred for about 2 h. The organic phase is separated off, the aqueous phase is extracted three times with 500 ml each of dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16](=[O:48])[N:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[NH:32][C:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CI.CN(C)C=O>O1CCCC1.O>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16](=[O:48])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[N:35]([CH3:1])[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:33]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:32]=1
Reactant: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1C)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
To a solution of potassium carbonate (0.056 g, 0.00042 mol) in dry tetrahydrofuran (10 mL) was added, portionwise as a solid, N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea (0.25 g, 0.00042 mol) and the reaction mixture was stirred at ambient temperature for 10 minutes. To this reaction mixture was added, dropwise, methyl iodide (0.039 mL, 0.0895 g, 0.00063 mol) and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was then treated with N,N-dimethylformamide (1.0 mL) and methyl iodide (0.1 mL) and the reaction mixture was stirred at reflux for an additional 24 hours. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed with 3:7 hexane-ethyl acetate to give the title compound (0.13 g, 0.00022 mol) as a yellow oil. 1H NMR (CDCl3) δ8.1-8.0(m,1H), 7.5-7.1(m,10H), 6.9-6.7(m,2H), 6.4(s,1H), 3.5(s,3H), 3.4-3.2(m,5H), 1.9-1.2(m,17H), 0.9(t,3H,J=8Hz).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:13][CH:14]=2)O1.[C:22]([O:26][C:27](=[O:38])[NH:28][C@H:29]([C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=1)[CH3:30])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.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]>[C:22]([O:26][C:27](=[O:38])[NH:28][C@H:29]([C:31]1[CH:32]=[CH:33][C:34]([C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:13][CH:14]=2)=[CH:35][CH:36]=1)[CH3:30])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CC1(C)OB(C2=CCN(C(=O)C(F)(F)F)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2=CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
400 mg of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoroacetyl)-1,2,3,6-tetrahydropyridine [154-2] was dissolved in 10 mL of N,N-dimethylformamide, then 196 mg of the t-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [106-1], 54 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), and 181 mg of potassium carbonate were added thereto, and stirred overnight at 80° C. The reaction mixture was cooled back to room temperature, then diluted in 100 mL of ethyl acetate, and washed with water and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, and the insolubles were filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 100 mg of t-butyl((1S)-1-{4-[1-(trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}ethyl)carbamate [154-3] as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(C(O)=O)CC[CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:31][CH2:30]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Reactant: O=C(O)C1CCC1
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCCCC1

Procedure:
Cyclohexane carboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (compound of Formula II where R1=cyclohexyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]amide (compound of Formula III where R1=cyclobutyl and Q1=Ph-(3-OBn)) above except for the substitution of cyclohexane carboxylic acid for cyclobutanecarboxylic acid; MS (ES) 436.2 (M+1), 438.2 (M+3).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C>[Br:22][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:10]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc2nc(-c3ccccc3)oc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2nc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 g (7.41 mmol) 7-methyl-2-phenyl-benzoxazole are dissolved in 5 ml glacial acetic acid, then 0.74 g (9.02 mmol) sodium acetate and 1.25 g (7.82 mmol) bromine are added. The mixture is stirred overnight at RT, then the solv. is eliminated by rotary evaporation in vacuo, the residue is dissolved with petroleum ether and extracted with water. The org. phase is dried on magnesium sulphate and evaporated down to ¼. The precipitated solid is suction filtered cold.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[C:4]([C:16](=[O:18])[CH3:17])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1nc(Br)ccc1F
Temperature: -65 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-Bromo-5-fluoro-pyridine (11 g, 62.5 mmol) was dissolved in diethyl ether at room temperature under a nitrogen atmosphere. The reaction mixture was cooled until the internal temperature was −66° C. Butyl lithium (2.5 M in hexanes, 26 mL, 65 mmol) was added dropwise over 0.5 h. The resulting reaction mixture was left at −65° C. for 1 h. N,N-Dimethylacetamide (6.5 mL, 70 mmol) was added over 10 min. and the reaction mixture was stirred at −65° C. for 2 h. 1M hydrochloric acid aq. (50 mL) was added and the mixture was warmed to room temperature. The pH was adjusted to 7 with additional hydrochloric acid. The aqueous phase was extracted with diethyl ether three times. The combined organic phases were washed with Brine, dried over sodium sulphate, and concentrated in vacuo. Purification by flash column chromatography (eluent heptane:diethyl ether gradient) yielded 4.6 g (34% yield) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](O[C@@H](C1C=C(Cl)C=CC=1C1C=CC=CC=1)C1CCN(C2C=CC(C(O)=O)=CC=2)CC1)(C(C)(C)C)(C)C.[CH2:75]([N:77]([CH2:80][C@H:81]1[N:86]([CH2:87][CH2:88][C@@H:89]([NH:98][C:99]2[CH:104]=[CH:103][C:102]([S:105]([NH2:108])(=[O:107])=[O:106])=[CH:101][C:100]=2[S:109]([C:112]([F:115])([F:114])[F:113])(=[O:111])=[O:110])[CH2:90][S:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH2:85][CH2:84][O:83][CH2:82]1)[CH2:78][CH3:79])[CH3:76]>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:108][S:105]([C:102]3[CH:103]=[CH:104][C:99]([NH:98][C@H:89]([CH2:88][CH2:87][N:86]4[CH2:85][CH2:84][O:83][CH2:82][C@H:81]4[CH2:80][N:77]([CH2:78][CH3:79])[CH2:75][CH3:76])[CH2:90][S:91][C:92]4[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=4)=[C:100]([S:109]([C:112]([F:113])([F:115])[F:114])(=[O:111])=[O:110])[CH:101]=3)(=[O:106])=[O:107])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
The title product (100 mg, yield: 55%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 89. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid, (INTERMEDIATE 13, 84 mg, 0.16 mmol) and 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 92, 100 mg, 0.16 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM for 19 minutes), providing the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1.[CH2:14](I)[CH3:15].CC(C)([O-])C.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH3:15])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1cc(N)c(I)c(O)c1
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(N)c1I
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-amino-5-hydroxy-4-iodo-benzoic acid methyl ester (0.25 g, 0.85 mmol) in DMF (3 mL) and ethyl iodide (0.10 mL, 0.146 g, 0.94 mmol) at 0° C. was added sodium tert-butoxide (0.11 g, 0.94 mmol) in small portions over a time period of 10 min. After stirring for 1 h, the cooling bath was removed and the reaction mixture stirred at rt for an additional 18 h. The solution was concentrated by evaporation under reduced pressure and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (2:1) yielding 0.19 g (69%) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(C(=O)OCc3ccccc3)c2n1
Temperature: 5 °C
Yield: 97.5 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.201 g, 1.0 mmol), benzyl chloroformate (0.20 mL, 1.1 mmol), triethylamine (0.21 mL, 1.5 mmol) and DMAP (15 mg) in DMF (10 mL) was stirred at room temperature for 4 h, poured into cold water, cooled for 30 min at 5° C. and the resulting solid filtered and dried at 40° C. to give the title compound (0.327 g, 98%) as a cream solid.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.CNC(C1C2C=C(C3C([Br:56])=CN=C([Cl:57])N=3)SC=2C=CC=1)=O>>[ClH:25].[ClH:57].[ClH:1].[CH3:4][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Br:56])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 517 (79Br) and 519 (81Br) [M(free base)+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:16]([CH3:15])(=[O:18])=[O:17])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 609 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then methanesulfonylchloride (1.18 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (ethyl acetate then chloroform-methanol, 95:5 v/v) to yield 1.6 g of the title compound in pure form.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=[O:3].[BH4-].[Na+]>C1COCC1.CO>[Br:11][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(Br)c1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromo-4-fluoroacetophenone (10 g, 46 mmol) in THF (100 mL) and methanol (1.0 mL) was added sodium borohydride (2.1 g, 55.5 mmol). The mixture was heated up to 70° C. for 1 h, then cooled down to rt. The reaction was quenched by 100 ml of 1N HCl solution and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 9.8 g of 84A (97% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=6.15 Hz, 3H) 7.24-7.33 (m, 1H) 7.59 (dd, J=6.59, 2.20 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:6]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:13][CH2:12]1)[C:7]([O:9]C)=O)[CH3:5].[OH-].[Na+]>CO>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([NH:30][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][C@H:14]4[CH2:13][CH2:12][C@H:11]([C@@H:6]5[N:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:7]5=[O:9])[CH2:16][CH2:15]4)[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)C(C1CCC(Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1)N(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@H]([C@H]2C(=O)NCCN2C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 700 mg methyl [(2-amino-ethyl)-methyl-amino]-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-acetate, 7 ml of methanol and 0.65 ml 4N sodium hydroxide solution is stirred for three hours at ambient temperature. Then the reaction mixture is evaporated down and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and evaporated down. The flask residue is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. ammonia (98/2/0.1 auf 8/2/0.1) as eluant. The crude product is stirred with diisopropylether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,2-dimethylpropanamide (27 mg, 0.064 mmol). 1H NMR (CDCl3-d) δ 1.35 (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H), 3.96 (s, 3H), 4.13(m, 2H), 4.97 (m, 1H), 5.46(bs, 2H), 6.98 (s, 1H), 7.04 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49 (d, J=8.2 Hz, 1H). LC/MS: MH+=424.