Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:12][O:13][CH:14]=[CH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSc1nccc(C=O)n1
Agent: [Cl-]
Product: COC=Cc1ccnc(SC)n1

Procedure:
Alternatively, intermediate 7 used in the synthesis of compounds of formula Ia can be prepared according to Schemes 2-4 below. 2-Methylsulfanyl-pyrimidine-4-carbaldehyde (8) can be condensed with (methoxymethyl)triphenylphosphonium chloride (Wittig reaction) to give 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine (9). Oxidation of (9) with N-bromosuccinimide in methanol provides 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (10). Condensation of (10) with 2-amino-3-chloropyrazine (1) in aqueous acid and a co-solvent such as acetone gives 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (11). Compound 11 can then be reacted with an appropriate amine (HNR1R2) either in excess or in the presence of another base, such as diisopropyl ethyl amine, in an appropriate solvent, such as ethanol or butanol, between room temperature to reflux to give the intermediate 7. Intermediate 7 can also be prepared via the ethyl homologs 9′ and 10′ according to Scheme 4 below. Compound 9′ (the ethyl homolog) can be prepared by the reaction ethyl ethynyl ether (13) with borane—tetrahydrofuran complex followed by palladium catalyzed coupling with 4-chloro-2-(methylthio)pyrimidine (12). Oxidation of 9′ with N-bromosuccinimide in ethanol provides the ethyl homolog 10′. Homolog 10′ can be converted to intermediate 7 in the same way as 10.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 4-bromo-N-methyl-2-nitroaniline (6 g, 25.97 mmol) in ethanol (100 ml) was added SnCl2.2H2O (29 g, 128.52 mmol). The resulting solution was stirred for 3 h at 70° C., adjusted to pH 8 with potassium hydroxide (4M), extracted with ethyl acetate (2×200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N1-methylbenzene-1,2-diamine as a white solid (5 g, 96%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O.O.C([O-])(=O)C.[Na+]>O.C(Cl)(Cl)Cl>[C:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
90.1 g of acrylic acid (1.25 mol), 29.8 g of 4-(6-hydroxyhexyloxy)benzoic acid, 4.5 g of hydroquinone, 4.5 g of p-toluenesulfonic acid and 300 ml of chloroform were placed in a sulfonation flask having a stirrer, water separator and reflux condenser. The mixture was heated to reflux for about 20 hours and then treated with a solution of 3.25 g of sodium acetate trihydrate in 10 ml of water. The chloroform and the excess acrylic acid were subsequently distilled off on a rotary evaporator. The residue was taken up in 1.5 1 of chloroform. The mixture was stirred for 2 hours and then filtered. The filtrate was washed three times with 200 ml of water each time, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 500 ml of toluene and the solution was again filtered. The filtrate was cooled to 4° C. for 12 hours and then to -20° C. for a further 12 hours. The crystalline product obtained was removed by filtration under suction, washed twice with cold toluene and again recrystallized from 400 ml of toluene. After drying at 60° C./40 mbar there were obtained 29.2 g of 4-(6-acrylyloxyhexyloxy)benzoic acid with m.p. (C-N) 92° C. and cl.p. (N-I) 110° C.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.C(O)C.[CH2:11]([NH2:13])[CH3:12]>C(O)C>[CH2:11]([NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (640 mg) in ethanol (6 mL) was added 30% ethanamine ethanol solution (722 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with 2-propanol to give the title compound (320 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C>[Pd].O1CCCC1>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1CC=C(c2cccnc2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 4-(2-fluoropyridin-3-yl)cyclohex-3-enol (750 mg, 3.88 mmol) and Ethanol (31.100 ml):Tetrahydrofuran (7.78 ml) was added 10% palladium on carbon, (240 mg, 2.255 mmol) before purging the reaction of air and backfilling with hydrogen. It was stirred for 3 h at room temperature before adding an additional 30 mol % Pd/C and stirring at 40° C. for 16 h. The reaction mixture was cooled and filtered through Celite before concentrating under reduced pressure to yield 4-(2-fluoropyridin-3-yl)cyclohexanol as a pale yellow oil that was used without purification. MS (ESI, pos. ion) m/z: 196.1 (M+1).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[N:14]3[C:21](=[O:31])[N:22]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[N:23]=[C:13]3[C:12]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([N:22]2[C:21](=[O:31])[N:14]3[C:15](=[O:20])[NH:16][C:17]4[CH:18]=[CH:19][C:10]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:11][C:12]=4[C:13]3=[N:23]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc3c4cc(C#Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of phenylacetylene (15.0 μg, 0.137 mmol) and 8a (25.3 mg, 0.0682 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(OAc)2 (1.53 mg, 6.82 μmol) and triphenylphosphine (3.57 mg, 13.6 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 13a as a white solid (14 mg, 70%). mp: >300° C. (decomp.),
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Temperature: -25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Commercially available 1-benzylpiperidin-4-one (78.5 g, 0.415 mol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled to −25° C. Ethyl diazoacetate (56.8 g) and boron trifluoride diethyl ether complex (128 mL) were simultaneously added dropwise to the solution over one hour, followed by stirring for one hour while elevating the temperature from −25° C. to 0° C. The reaction mixture was mixed with a saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) and thereby yielded ethyl 1-benzyl-5-oxoperhydroazepine-4-carboxylate (30.6 g, in a yield of 27%).
Reaction SMILES: C([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:9]1=2)C1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[OH:24][CH2:23][C:20]1[CH:21]=[CH:22][C:9]2[NH:8][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)CCc1ccccc1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
5-Benzyl-2-formyl-10,11-dihydro-5H-dibenz[b,f]azepine (3.29 g) was dissolved in 200 m. of ethanol, and 0.5 g of sodium borohydride was added to the solution, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with dichloromethane. The mixture was washed with 1N aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in 300 ml of ethanol. To the solution was added 300 mg of 10% palladium carbon and the mixture was stirred in a stream of hydrogen for 4 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 1.0 g (42%) of the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:15]([CH2:14][C:11]1[CH:12]=[N:13][C:8]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1nccs1
Reactant: CN(Cc1ccc(Cl)nc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CN(Cc1ccc(Nc2nccs2)nc1)C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 60.4 %

Procedure:
A suspension of 2-aminothiazole (0.556 g, 5.55 mmol, 1.15 eq), tert-butyl (6-chloropyridin-3-yl)methyl(methyl)carbamate (1.24 g, 4.83 mmol), sodium carbonate (0.717 g, 6.76 mol, 1.4 eq) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (0.034 g, 0.058 mmol, 0.012 eq) in THF (12 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzyl ideneacetone)dipalladium (0) (0.018 g, 0.019 mmol, 0.004 eq) was then added to the suspension which was heated at 130° C. for 18 hours. Tris(dibenzylideneacetone) dipalladium (0) (0.018 g, 0.019 mmol, 0.004 eq) and 9,9-dimethyl-4,5-bis(diphenyl phosphino)xanthene (XANTPHOS) (0.034 g, 0.058 mmol, 0.012 eq) were added again and the reaction was stirred for 18 more hours. The same was repeated a second time. The mixture was cooled down to RT and filtered. The THF filtrate was evaporated and the residue (1.72 g) was purified on Biotage silica gel chromatography (hexane/ethyl acetate 1:1 to 0:1) to give the title material (0.934 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm: 1.52 (9H, s), 2.84 (3H, s), 4.40 (2H, s), 6.86 (1H, d, J=3.54 Hz), 6.92 (1H, d, J=8.59 Hz), 7.44 (1H, d, J=3.79 Hz), 7.57 (1H, d, J=19.45 Hz) 8.27 (1H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:27])([CH3:26])[CH2:3][C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:26])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NC(=O)C(C)(C)C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 688 using pivalic acid. LC-MS Method 1 tR=2.05 min, m/z=515; 1H NMR (CDCl3) 7.36-7.27 (5H, m), 7.22 (2H, d, J=8.5 Hz), 6.79 (2H, d, J=8.2 Hz), 6.20 (1H, s), 5.58 (1H, q, J=7.0 Hz), 2.79 (1H, m), 2.44 (1H, d, J=15.5 Hz), 2.37 (1H, d, J=15.2 Hz), 2.24-2.06 (3H, m), 1.47 (3H, d, J=7.03 Hz), 1.37 (3H, s) 1.10 (9H, s), 1.05 (3H, s).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2Cl)=[N:14][C:13]([Cl:18])=[CH:12][CH:11]=3)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]2)=[N:24][CH:25]=1>>[Cl:18][C:13]1[N:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])=[C:16]2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 91.8 %

Procedure:
Following general procedure I, cyclobutyl(4,6-dichloro-1,5-naphthyridin-3-yl)methanone (200 mg, 0.71 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (311 mg, 1.1 mmol) to afford the desired product (350 mg, 78%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.52 (s, 1H), 8.88 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.31 (dd, J=9.0, 2.7 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.81 (br s, 1H), 4.15-3.97 (m, 1H), 3.91-3.60 (m, 3H), 3.58-3.31 (m, 2H), 2.54-2.21 (m, 4H), 2.20-2.00 (m, 1H), 2.00-1.85 (m, 2H), 1.82-1.63 (m, 2H), 1.51 (s, 9H); ESI MS m/z 537 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[C:30]([NH2:37])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:4]1[C:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=[C:2]([NH:37][C:30]2[C:31]3[O:36][CH2:35][CH2:34][O:33][C:32]=3[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: COc1ccc(CN2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc(N2CCOCC2)c2c1OCCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN2CCc3c(Cl)nc(Nc4ccc(N5CCOCC5)c5c4OCCO5)nc32)cc1
Yield: 60.9 %

Procedure:
According to General Protocol II, 4-chloro-7-(4-methoxybenzyl)-N-(8-morpholino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyrimidin-2-amine was prepared from 2,4-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (Intermediate A1, 200 mg, 0.645 mmol), 8-morpholino-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (Intermediate B4, 152 mg, 0.644 mmol), Pd2(dba)3 (118 mg, 0.129 mmol), (±)-BINAP (80 mg, 0.129 mmol) and sodium tert-butoxide (124 mg, 1.292 mmol) in a microwave tube at 100° C. for 10 minutes, and isolated as a yellow solid (200 mg, yield 61%). 1H NMR (400 MHz, CDCl3) δ ppm 8.01-8.03 (d, 1H, J=8.8 Hz), 7.21-7.24 (d, 2H, J=8.4 Hz), 6.86-6.88 (d, 2H, J=8.8 Hz), 6.51-6.54 (d, 1H, J=8.8 Hz), 4.54 (s, 2H), 4.30-4.34 (m, 4H), 3.86-3.89 (m, 4H), 3.80 (s, 3H), 3.46-3.50 (m, 2H), 3.00-3.03 (m, 4H), 2.91-2.95 (m, 2H).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[CH2:22][CH2:23][S:24](=[O:42])(=[O:41])[C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:37]=[CH:36][C:35]7[O:38][CH2:39][O:40][C:34]=7[CH:33]=6)=[CH:28][C:26]=5[CH:27]=4)=[O:20])=[CH:14][CH:13]=3)[CH3:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:39]1[O:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:30]=[CH:31][C:25]4[S:24](=[O:41])(=[O:42])[CH2:23][CH2:22][C:21]([C:19]([NH:18][C:15]5[CH:16]=[CH:17][C:12]([CH2:11][N:9]([CH3:10])[CH:6]6[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]6)=[CH:13][CH:14]=5)=[O:20])=[CH:27][C:26]=4[CH:28]=3)=[CH:33][C:34]=2[O:40]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCO5)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCO5)ccc3S(=O)(=O)CC2)cc1)C1CCC(=O)CC1
Reaction time: 39 h
Yield: 61.2 %

Procedure:
To a solution of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(3,4-methylenedioxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (100 mg) in THF (10 ml) was added at room temperature 3N hydrochloric acid (1 ml), and the mixture was stirred for 39 hours. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless solid which were recrystallized from ethyl acetate to give colorless crystals of 7-(3,4-methylenedioxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 21) (56.8 mg).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CI.[CH2:9]([O:11][C:12]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:20](O)[C:19]2[C:14](=[CH:15][C:16]([C:34]([F:37])([F:36])[F:35])=[CH:17][CH:18]=2)[N:13]=1)[CH3:10].CCOC(C)=O.CCCCCC>CN(C=O)C.O>[CH2:9]([O:11][C:12]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:20]([O:4][CH3:1])[C:19]2[C:14](=[CH:15][C:16]([C:34]([F:36])([F:37])[F:35])=[CH:17][CH:18]=2)[N:13]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCOc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1nc2cc(C(F)(F)F)ccc2c(OC)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
300 mg (2.2 mmol) K2CO3 and 0.9 ml (14.6 mmol) methyliodide were added to a solution of 300 mg (0.7 mmol) 2-ethoxy-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoro-methyl)quinoline-3-carboxylic acid amide in DMF (5 ml) and the mixture was stirred for 16 h at RT. The mixture was subsequently diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:12) of the residue, 240 mg (0.6 mmol, 81%) 2-ethoxy-N-[(3-fluorophenyl)-methyl]-4-methoxy-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 12) was obtained. MS: m/z 423.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCCN(c2ccc(C#N)cc2)CC1

Procedure:
4-Fluorobenzonitrile (25.5 g), 4-methylhomopiperazine (26.2 ml) and potassium carbonate (28 g) were heated in DMSO for 15 hr. After heating, the reaction mixture was poured into water (1 L). The precipitated crystals were collected by filtration to give the objective 4-(4-methylhomopiperazin-1-yl)benzonitrile (34.6 g), melting point 82-84° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([N:13]([CH3:28])[CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11](=[O:12])[N:13]([CH3:28])[CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1)[CH3:30]
Reactant: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)Cc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(CC(=O)N(C)CC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 b], 2-(1H-indol-6-yl)-N-methyl-N-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-acetamide was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate and potassium iodide in acetonitrile under reflux conditions to give the title compound as orange crystals.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C([N:23](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.N>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH2:23])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Suspend Boc-(L)-Pal-OH (1.34 g, 5 mmol) in methylene chloride (50 mL) and cool to -15° C. Add diisopropylethylamine (963 μl, 5.5 mmol) and isobutylchloroformate (715 μL, 5.5 mmol). Stir the mixture 15 minutes at -15° C. Pass through the solution a vigorous stream of anhydrous ammonia (over solid sodium hydroxide) for about 3 minutes. Stir the mixture 10 minutes at -15° C. and 20 minutes at room temperature. Evaporate methylene chloride, add ethyl acetate (70 mL) and wash with saturated aqueous solution of sodium bicarbonate. Dry over magnesium sulfate and evaporate. Crystallize from ethyl acetate/hexane to give Boc-(L)-Pal-NH2 (0.98 g, 75%).