Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(=O)C1C=CC([C@@H](N2CCN(CC=C)CC2)C2C=CC=C(N[CH2:50][C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)C=2)=CC=1)C>CO>[CH:29]1([CH2:28][N:25]2[CH2:26][CH2:27][N:22]([C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:50][C:51]4[S:52][CH:53]=[CH:54][CH:55]=4)[CH:3]=3)[C:9]3[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:23][CH2:24]2)[CH2:30][CH2:31]1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CC3CC3)CC2)cc1
Reactant: C=CCN1CCN([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NCc3cccs3)c2)CC1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NCc3cccs3)c2)N2CCN(CC3CC3)CC2)cc1

Procedure:
Synthesized using COMPOUND 68 and the method described for COMPOUND 69. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; (400 MHz, CD3OD) 0.39-0.44 (m, 2H), 0.72-0.78 (m, 2H), 1.04-1.10 (m, 1H), 1.07-1.11 (m, 3H), 1.22 (t, J=6.99 Hz, 3H), 2.20-2.36 (m, 2H), 2.91-3.08 (m, 2H), 3.04 (d, J=7.49 Hz, 2H), 3.06-3.19 (m, 2H), 3.21-3.30 (m, 2H), 3.46-3.60 (m, 4H), 4.33 (s, 1H), 4.52 (s, 2H), 6.62 (dd, J=8.00, 2.44 Hz, 1H), 6.77 (d, J=7.58 Hz, 1H), 6.83 (t, J=1.81 Hz, 1H), 6.94 (dd, J=5.04, 3.53 Hz, 1H), 6.98-7.00 (m, 1H), 7.07 (t, J=7.80 Hz, 1H), 7.25 (dd, J=5.00, 122 Hz, 1H), 7.30 (d, J=8.17 Hz, 2H), 7.50 (d, J=8.16 Hz, 2H). Found. C, 53.58; H, 5.46; N, 7.10. C31H40N4OS×0.70H2O 2.4CF3COOH has C, 53.55; H, 5.50; N, 6.98%. [a]D20=−19.74 deg [c 0.947, MeOH]
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:37][O:38][CH2:39][CH3:40])[N:15]([CH2:16][C:17]3([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>C(O)C>[CH2:39]([O:38][CH2:37][C:14]1[N:15]([CH2:16][C:17]2([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=1)[CH3:40]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A solution of HCl in ethanol (4.2 M, 0.8 mL, 3.56 mmol) was added to a suspension of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate (0.40 g, 0.71 mmol) in ethanol (4 mL) at rt. The resulting yellow solution was heated at reflux for 1.5 h. The reaction was stirred at rt for 16 h, then was concentrated under reduced pressure. The resulting solid was dissolved in water (20 mL) and 20% aqueous NaOH was added until the pH=13. The solution was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a solid that was crystallized from acetonitrile. The crystals were dried under vacuum at 65° C. to provide 2-(ethoxymethyl)-1-({4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.25 g, 76%) as crystalline plates, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.61 (bs, 2H), 4.85 (s, 2H), 4.81 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.5 Hz, 2H), 3.19 (t, J=5.6 Hz, 2H), 2.92 (s, 3H) 2.66-2.58 (m, 4H), 1.84 (bs, 1H), 1.70-1.66 (m, 2H), 1.48-1.38 (m, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (APCI) m/z 462 (M+H)+; Anal. Cacld for C22H31N5O4S: C, 57.25; H, 6.77; N, 15.17. Found: C, 57.48; H, 7.05; N, 15.57.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>CN(C=O)C>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]3)=[CH:15][CH:14]=2)[CH2:5][CH2:6]1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCCN3CCOCC3)ccc12
Temperature: 50 °C

Procedure:
A mixture of N-(2-hydroxyethyl)morpholine (2.66 ml), sodium hydride (60% dispersion in mineral oil, 0.88 g) and DMF (25 ml) was warmed to 50° C. for 3 minutes. The resulting solution was allowed to cool for 10 minutes before a solution of 7-fluoro-3,4-dihydroquinazolin-4-one (1.64 g) in DMF (25 ml) was added and the resultant mixture was heated to 125° C. for 18 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and 2N hydrochloric acid solution. The organic phase was dried and evaporated to give 7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-one (1.58 g); NMR Spectrum: (CDCl3) 2.6 (t, 4H), 2.87 (t, 2H), 3.73 (t, 4H), 4.25 (t, 2H), 7.12 (m, 2H), 8.07 (s, 1H), 8.19 (d, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([C:15]1[CH:20]=[CH:19][C:18]([N+]#N)=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([N+]#N)=[CH:9][CH:8]=1.F[B-](F)(F)F.[CH2:28]([C:31]#[N:32])[CH:29]=[CH2:30].O>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([CH2:28][CH:29]=[CH:30][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:15]2[CH:20]=[CH:19][C:18]([CH:30]=[CH:29][CH2:28][C:31]#[N:32])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:32]
Reactant: N#[N+]c1ccc(Cc2ccc([N+]#N)cc2)cc1
Reactant: C=CCC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCO
Product: N#CCC=Cc1ccc(Cc2ccc(C=CCC#N)cc2)cc1
Temperature: 40 °C
Yield: 60.8 %

Procedure:
A suspension of 4,4′-methanediyl-bis-benzenediazonium tetrafluoroborate (11.9 g, 0.03 mol), prepared according to the method of example 6.1, allyl cyanide (8.05 g; 0.12 mol), and palladium acetate (0.135 g, 0.6 mmol) in 80 ml of ethanol is heated at 40° C. during 22 h. The heterogeneous reaction mixture is poured into 300 ml of water, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated. The crude beige product is recrystallized from 130 ml of ethanol, yielding 5.44 g (61%) of 4-{4-[4-(3-cyano-propenyl)-benzyl]-phenyl}-but-3-enenitrile as light beige crystals, melting point 128-130° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1>CN(C=O)C>[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[CH2:51][CH2:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 49% yield: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH:11]=[O:12])=[CH:6][CH:7]=1
Reactant: C=C(CCCO)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(CCC=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
A mixture of 4-(4-chlorophenyl)pent-4-en-1-ol (5.5 g) and pyridinium dichromate (14.62 g) in dichloromethane (50 ml) was stirred at room temperature for 24 hours. The mixture was diluted with diethyl ether and the solid material was filtered off. The filtrate was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(4-chlorophenyl)pent-4-enal (2.6 g, 48%) as a yellow oil, 1H nmr (CDCl3): 9.75 (1H, broad singlet, CHO), 1R (film): 1720 cm-1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[C:25]1([CH3:28])[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1.[C:25]1([CH3:28])[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Yield: 93 %

Procedure:
(S)-2-(4-p-Tolyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.02 g, 7.88 mmol) was taken into 4M HCl in dioxane (10 mL) and reacted at room temperature for 12 h. The mixture was concentrated to dryness to obtain the title product (2.35 g, 7.35 mmol, 93% yield); MS; m/z 320. found 284 (M-36 HCl). 1H NMR (400 MHz, DMSO-d6) δ 1.70-1.78 (m, 1H), 1.87-1.94 (m, 1H), 1.96-2.01 (m, 1H), 2.08-2.14 (m, 1H), 2.27 (s, 3H), 3.17-3.24 (m, 2H), 3.86-3.92 (m, 1H), 4.10-4.15 (m, 1H), 4.20-4.24 (m, 1H), 6.82-6.84 (d, J=8.0, 2H), 6.99-7.0 (m, 4H), 7.15-7.17 (d, J=8.0, 2H), 9.34 (s, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:14])[CH2:5][CH:4]2[CH3:3]
Reactant: CC1CC(=O)Nc2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1CC(=O)Nc2ccc(Br)cc21
Reaction time: 2 h

Procedure:
A solution of bromine (0.08 cm3) in acetic acid (1 cm3) was added at room temperature to a stirred solution of 4-methyl-3,4-dihydro-2-(1H)-quinolone (0.5 g) in acetic acid (4.0 cm3). After 2 hours, volatile material was removed in vacuo, the residue was partitioned between chloroform (50 cm3) and water (20 cm3), and the organic phase was further extracted with chloroform (2×20 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo and the solid residue was recrystallised from ethyl acetate to afford 6-bromo-4-methyl-3,4-dihydro-2-(1H)-quinolone, m.p. 190°, (0.35 g).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1>>[F:1][C:2]1[C:20]([N:35]2[CH2:34][CH2:33][NH:32][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][O:23][CH3:22])=[CH:30][CH:29]=3)[CH2:36]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: COCc1ccc(C2CNCCN2)cc1
Product: COCc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CCN2)cc1
Yield: 89.3 %

Procedure:
Using the procedure described in Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.16 g) and (RS)-2-[4-(methoxymethyl)phenyl]piperazine (1.82 g), (RS)-7-fluoro-8-{3-[4-(methoxymethyl)phenyl]-1-piperazinyl}-1-methyl-4-oxo -1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.70 g) is obtained in the form of a yellow solid, decomposing at 284° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:20][C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=3[N:21]=2)[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)C(O)c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: OC(c1cccc(Br)c1)c1nc2cc(F)ccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (3.7 g) and 4-fluoro-ortho-phenylenediamine (2 g) in 5N aqueous hydrochloric solution (3.2 mL) is heated under reflux for 15 h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 90/10/0.5) to afford the pure 3-bromophenyl(5-fluoro-1H-benzimidazol-2-yl)methanol.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH:17]1([C:23](O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([C:23]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)C1CCCCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(C2CCCCC2)o1
Yield: 82 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using cyclohexanecarboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 233 mg, 82%) which was obtained as a white solid. MS: m/e 362.3 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Br)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]>O>[CH3:6][CH2:5][CH2:4][CH2:3][Sn:7]([O:1][Sn:7]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [OH-]
Reactant: CCCC[Sn](Br)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Temperature: 60 °C
Yield: 92.8 %

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 450 g of 30% aqueous sodium hydroxide solution and 300 g of tri-n-butyltin bromide containing 3.5% di-n-butyltin dibromide, with stirring and heating at 60° C., to perform hydrolysis for 60 minutes. To the resulting reaction mixture was added 260 g of water for specific gravity adjustment. The same precipitation as in Example 1 took place, and the reaction mixture split into three distinct phases. The specific gravity of the aqueous phase was measured and was found to be 1.25. Thereafter, the upper phase was treated in the same manner as in Example 1 to give 224.4 g (92.8% yield) of bis(tri-n-butyltin) oxide. Analysis revealed that the product was of high quality, its purity being 98.3% and the content of di-n-butyltin oxide dissolved therein being 300 ppm.
Reaction SMILES: O(C)[Na].[C:4]([C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:9][CH:10]=1)#[N:5].Cl.Cl.[C:22]1(N)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].O>CO>[NH:5]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]=[C:4]1[C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[S:9][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)NCc1nc(C#N)cs1
Agent: CO[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc(-c2nc3ccccc3[nH]2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to the preparation of 8, 1.89 g of a 30% NaOCH3 solution were added to tert-butyl (4-cyano-1,3-thiazol-2-yl)methylcarbamate (2.5 g; 10.45 mmol) in 25 ml of CH3OH, and the mixture was stirred at room temperature for 2 h. Addition of 1.9 g of 1,2-phenylenediamine bishydrochloride was followed by stirring overnight, and then the reaction mixture was added to 100 ml of H2O, and the solid resulting after filtration was dried in vacuo.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: N#CC=Cc1cncc(N2CCOCC2)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E & Z)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; LC/MS=531 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:28])([F:27])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH2:24]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:28])=[CH:21][CH:20]=2)=[O:26])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-trifluoromethoxyphenyl)-2-chloroacetamide (51 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced the residue was purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.35 (d, J=6 Hz, 2H), 7.55 (t, J=6 Hz, 1H), 7.76 (m, 2H), 8.12 (d, J=5 Hz, 1H), 9.98 (s, 1H); MS (ESI/APCI+) m/e 381 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].COC1C=CC(C[NH2:30])=CC=1>CN(C=O)C.C(O)(C(F)(F)F)=O>[NH2:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(OCc1ccccc1)c1c(Cl)c2ccccc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(C(=O)OCc2ccccc2)c(=O)[nH]c2ccccc12
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 116.5 %

Procedure:
Benzyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 66b) (0.55 g, 1.75 mmol) was dissolved in DMF (8 mL) and 4-methoxybenzylamine (0.56 mL, 4.31 mmol) was added. The reaction was heated at 115° C. for 30 minutes, then cooled to room temperature and poured into ice water. The resultant precipitate was dissolved in 10 mL TFA and stirred at room temperature for 15 minutes, then the mixture was poured into ice water. The resultant precipitate was collected, dissolved in dichloromethane, dried over MgSO4, filtered and evaporated to give the crude benzyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (600 mg) which was used as this without further purification. MS 295 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH2:12])[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:19]12[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:24]C(=O)O[C:20]2=[O:21]>CC#N>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:20](=[O:21])[C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:24])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-Aminomethyl-cyclohexanecarboxylic acid methyl ester (21.7 g, 127 mmol) in CH3CN (500 mL), K2CO3 (35 g, 254 mmol) and isatoic anhydride (20.7 g, 127 mmol) were added. The reaction was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure and the residue was washed with 200 mL of H2O and the solid obtained was filtered. The titled compound (31.1 g, quantitative yield) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][N:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][N:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: Cc1csc2c(NN(C)C)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NN(C)C)c2scc(C)c2n1
Yield: 92.5 %

Procedure:
150 mg (0.62 mmol) of 2-chloro-7-methyl-4-(2,2-dimethylhydrazino)thieno[3,2-d]pyrimidine and 564 mg (9.89 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 151 mg (yield: 92.6%) of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[OH:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1
Reactant: COc1ccc(C2=NNC(=O)CC2COCc2ccccc2)c2cc(C(F)(F)F)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NNC(=O)CC2CO)c2cc(C(F)(F)F)nn12
Yield: 25.3 %

Procedure:
The compound of Example 322 (60 mg) was dissolved in ethanol (25 mL) and ethyl acetate (25 mL). To this solution, 10% palladium carbon (30 mg) was added and the mixture was stirred at room temperature for 8 hours in a stream of hydrogen gas (1 atm). The insoluble material was removed by filtration through Celite. Evaporation of the solvent and subsequent purification by thin-layer chromatography (silica gel, ethyl acetate:methanol=10:1) afforded the title compound as a pale yellow powder (12 mg).