Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])[N:14]([CH2:15][CH2:16][CH2:17]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])[N:14]([CH2:15][CH2:16][CH2:17][NH:12][CH2:11][CH2:10][N:14]([CH3:15])[CH3:13])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCN(C)C

Procedure:
A mixture of the product from step (v) (0.96 g) and thionyl chloride (10 mL) in DCM (20 mL) was heated under reflux for 6 h then evaporated under reduced pressure. The residue was dissolved in acetonitrile (20 mL) then N,N-dimethylethylenediamine (10 mL) added and the mixture heated under reflux for 24 h. The solvent was removed under reduced pressure and the residue purified by RPHPLC, yield 0.512 g.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(I)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml, 395 mmol)were combined, stirred at 70° C. for 8 h and then heated at reflux for 48 h. The solution was poured into ethyl acetate (300 mL) and washed with 1N hydrochloric acid (3×200 mL). The aqueous layers were combined and extracted with ethyl acetate (1×100 mL). The combined ethyl acetate extracts were washed with saturated ammonium chloride (2×200 mL), dried over magnesium sulfate and concentrated in vacuo yielding a dark red oil. This oil was purified by flash chromatography using ethyl acetate-hexanes (3:7) yielding a red oil. Crystallization of this oil from hexanes yielded the title compound as light red crystals (8.3 g, 31%): mp 105-106° C. 1H NMR (CDCl3 /300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70 (q, 1H, J=6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS 415.9926 (M+NH4+ Calc'd 396.9746)
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][CH3:20]>O1CCOCC1>[NH2:14][C:11]1[N:10]=[C:9]([NH:21][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][N:12]=1
Reactant: CCCCCN
Reactant: Nc1ncc(Cc2ccccc2)c(Cl)n1
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)ncc1Cc1ccccc1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 5-benzyl-4-chloropyrimidine-2-ylamine (350 mg, 0.74 mmol), amylamine (0.74 ml) and dioxane (4 ml) was kept at 90-100° C. for 8 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with ether and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH:CHCl3=70:1) to give the object compound (355 mg, 82.2%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:10]([C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[S:2]([N:1]=[C:19]=[O:20])(=[O:3])=[O:4])([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(S(N)(=O)=O)CCC1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1

Procedure:
In 75 ml of dry xylenes was placed 4.0 g of methyl 2-(aminosulfonyl)-1-cyclopentene-1-carboxylate (VIII), 6.5 ml of n-butyl isocyanate, and 0.05 g of DABCO. The mixture was heated to reflux (ca 138°) then contacted with an excess of phosgene which was condensed into the mixture from a dry-ice condenser until the reflux temperature dropped to 126°. Over several hours the temperaure increased to 135° and additional phosgene was condensed into the mixture, again, lowering the temperature to 129°. This process was repeated until no temperature increase could be observed, indicating complete consumption of the sulfonamide. The mixture was then cooled and the xylenes removed under reduced pressure to yield ca 5 g of an amber oil. An infrared spectrum (neat) exhibited a strong absorption at 2230 cm-1 indicating the title compound.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51.2 mg, 0.134 mmol), 3-methoxytetrahydro-4H-pyran-4-one (70 mg, 0.40 mmol) and triethylamine (0.0374 mL, 0.269 mmol) in dry methylene chloride (5.0 mL, 0.078 mol) was treated with sodium triacetoxyborohydride (85.4 mg, 0.403 mmol) at room temperature under N2 overnight. The reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer 26.3 mg; second isomer: 17.3 mg. LC-MS calculated for C26H36F3N3O3: (M+H) 496; found 496.2 for both isomers.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:9][CH:10]([CH3:18])[C:11](=[O:17])[CH2:12][C:13](OC)=[O:14].[O-]CC.[Na+].Cl>C(O)C>[C:11]([CH:12]1[CH2:2][C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[O:1][C:13]1=[O:14])(=[O:17])[CH:10]([CH3:18])[CH3:9]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: C1CC2(CCO1)CO2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(=O)C1CC2(CCOCC2)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6.6 g 1,6-Dioxaspiro[2.5]octane and 8.2 ml methyl 4-methyl-3-oxopentanoate are dissolved in 30 ml ethanol, cooled to 0° C. and treated in portions with 3.9 g sodium ethoxide. After completion of the addition the mixture is warmed to room temperature and stirred for 18 hours. Then the mixture is poured in 200 ml ice water, acidified to pH 3 by addition of 1 M hydrochloric acid and extracted for three times with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:24](=[O:31])[NH:23][C:22]1=[O:32].C(N(C(C)C)CC)(C)C>C(O)(C)C>[S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:18][CH2:19][CH2:20][N:21]3[C:25]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:24](=[O:31])[NH:23][C:22]3=[O:32])[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: NCCN1C(=O)NC(=O)C12CCCCC2
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C1NC(=O)C2(CCCCC2)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 170 °C

Procedure:
A mixture of 4-benzo[b]thiophen-2-yl-5-bromo-2-chloro-pyrimidine (318 mg, 1.0 mmol) and 1-(2-aminoethyl)-1,3-diaza-spiro[4.5]decane-2,4-dione (214 mg, 1.01 equiv.) in isopropyl alcohol (4 mL) was treated with diisopropylethylamine (192 μL, 1.1 equiv.) and heated at 170° C. for 17 min in a Personal Chemistry microwave reactor. Upon cooling, the product was obtained by filtration and washing with isopropyl alcohol, recrystallizing from hot isopropyl alcohol. MS (M+H)+ 500/502.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 86 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (Example 2 Step 1) and 4-acetylphenylboronic acid according to the procedure described for Example 2 Step 2. Reaction conditions: 4 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 50/50 as eluent to afford 1-(4-chlorobenzyl)-5-(4-acetylphenyl)pyridin-2(1H)-one (0.29 mmol, 0.10 g, 86%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27]C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]4[CH2:26][CH2:27][CH2:32][CH2:31][CH2:30]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCCC4)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A suspension of 1.30 g (3.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 13 ml of N,N-dimethylformamide was treated with 1.44 g (0.017 mol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether/n-hexane. There were obtained 1.39 g (95%) of 7-chloro-8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 210°-212° (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Br:11])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(Br)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40° C. After 15 minutes, the mixture is washed with H2O (4×100 ml). The solution is dried (MgSO4) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59°-62° C. A 35 g sample of this material in 180 ml of dry dimethylformamide is stirred and heated at reflux with 17.57 g of Cu2 (CN)2 for 6 hours under N2 atmosphere. Subsequently, 180 ml of FeCl3 /HCl solution (40 g FeCl3.6H2O/10 ml concentrated HCl/60 ml H2) is added and the mixture is heated for 20 minutes at 60°-70° C. and poured into 350 ml of H2O. The aqueous mixture is extracted with CH2Cl2 and the extracts are washed with H2O, saturated NaHCO3 solution and H2O, respectively. The CH2Cl2 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to afford 14.25 g, mp 155°-159° C., of 4-amino-3-cyanoacetophenone. A 4.8 g sample of this product in 100 ml of EtOAc and 100 ml of CHCl3 containing 13.32 g of CuBr2 is heated at reflux temperature for 20 minutes. The mixture is further heated after 20 ml of EtOH is added and then filtered while still hot. The filter cake is washed with 50 ml of hot 20% MeOH/CH2Cl2 and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH2Cl2 and the solid is collected and washed with CH2CL2 to give 8.08 g of the phenacyl bromide. This material is added to 50 ml of t-BuNH2 in 100 ml of EtOH at 5° under N2 atmosphere. After 10 minutes of stirring, the mixture is allowed to warm to 30° C. to give a solution. This solution is cooled to 10° and 4 g of NaBH4 is added in portions. After 45 minutes, the mixture is allowed to warm (42° C.) and kept at 20° C. until the exotherm subsides. The mixture is then evaporated to dryness and the residue is washed with H2O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution is filtered. The filter cake is further washed with hot MeOH and the combined filtrates are concentrated to afford crystals. This solid is recrystallized from MeOH/2-PrOH to afford 2.08 g, mp 184°-186° C., of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Br:10])=[CH:4][C:3]=1[NH:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Br:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:12]=3[NH:11][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(Nc2cc(Cl)ccc2C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)Nc1cc(Cl)ccc1C(=O)N2
Yield: 102.3 %

Procedure:
A mixture of Example 223F (0.35 g, 0.94 mmol), HATU (0.430 g, 1.13 mmol), and excess Et3N in 4 mL of DMF was stirred overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtrated and concentrated to give 0.34 g of the title compound. MS (DCI) m/e 248 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.90 (s, 1H), 7.67 (d, J=8.42 Hz, 1H), 7.19 (s, 1H), 7.00 (d, J=1.87 Hz, 1H), 6.93 (dd, J=8.42, 2.18 Hz, 1H), 6.75 (s, 1H), 5.22 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C(N)CN>>[Si:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CO[Si](CCCNCCN)(OC)OC
Solvent: NCCN
Product: CO[Si](CCCNCCNCCC[Si](OC)(OC)OC)(OC)OC
Temperature: 140 °C
Yield: 972.3 %

Procedure:
A 2 liter, 3-necked reaction flask equipped with a magnetic stirrer, electric heating mantle, dropping funnel and water condenser, containing 22.0 grams of NH2CH2CH2NH(CH2)3Si(OCH3)3 was heated to 140° C. whereupon the addition thereto of 198.0 grams of 3-chloropropyltrimethoxy silane (Cl(CH2)3Si(OCH3)3) was commenced. Cl(CH2)3Si(OCH3)3 was introduced dropwise to the reaction flask over a period of 1 hour while maintaining a temperature of 145° C. to 150° C. by the occasional application of a water bath. The resultant mixture was cooled to 75° C., and 90 grams of anhydrous ethylenediamine was added to the cooled mixture. Thereafter, the mixture was allowed to separate into layers with the upper product containing layer being separated therefrom and stripped by vacuum distillation of lowboiling volatiles to yield 370 grams of (CH3O)3SiC3H6NHC2H4NHC3H6Si(OCH3)3. Amine titration and 13C NMR and 29Si NMR analysis verified the assigned structure of the resultant product.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:30][N:31]1[C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][N:33]=[CH:32]1>>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:35]5[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Agent: Cl
Product: Cn1cncc1-c1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)amine hydrochloride and (3-methyl-3H-imidazol-4-yl) tri-n-butylstannane; δH [2H6] DMSO 11.85(1H,bs), 9.25(1H,s), 9.19(1H,s), 9.02(1H,d), 8.93(1H,s), 8.16(2H,d), 8.06(2H,d), 7.78(1H,d), 7.61(1H,dd), 7.22(5H,m), 5.66(2H,s) 3.92 (3H,s); m/z (M+1+) 432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:22]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c(C)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4,6-trimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2Cl)=[O:15])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:9][N:8]=1.CN(C=O)C>O>[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[S:4][CH2:2][CH3:3])=[O:15])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:9][N:8]=1
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cnccc1Cl
Reactant: CCS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
289 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 828 mg of 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide and 4 ml of DMF was added under ice cooling, then the mixture was heated to room temperature, and stirred for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 700 mg of 4-ethylsulfanylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:41]1COCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][O:12][CH3:41])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CO
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1COC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of Example 23 (N-{4-[4-amino-7-(hydroxymethyl)-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)-phenyl]urea (22 mg, 0.04 mmol)) in anhydrous THF (1 mL) and CH2Cl2 (1 mL) was added SOCl2 (0.006 ml, 0.08 mmol). After 20 min, analytical HPLC shoved half of the starting material remained. Additional SOCl2 (0.01 ml) was added and the reaction was stirred at rt for 2.5 h until completion. The mixture was evaporated to dryness and CH2Cl2 (3 ml) was added. The solvent was evaporated to dryness and the crude concentrate was re-suspended in CH2Cl2 and evaporated to remove the excess SOCl2 completely. To the resulting solid was added anhydrous MeOH (1 ml) and Hunig's base (0.008 ml), the reaction was stirred at 70° C. overnight. After 16 h, the reaction was cooled to rt and solvent was evaporated. The crude material was taken up in ethyl acetate, washed with aq. saturated sodium bicarbonate three times and dried over Na2SO4. After concentration, the resulting crude was purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 12 mg of the title compound (yield 53%). 1H-NMR (DMSO-d6) δ 9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (dd, J=7, 3 Hz, 1H), 7.92 (s, 1H), 7.59 (t, J=3 Hz, 2H), 7.57 to 7.32 (m, 4H), 4.73 (s, 2H), 4.28 (s, 2H), 3.26 (s, 3H), 3.24 (s, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.84 min
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][C:12]3[N:17]=[CH:18][C:19]([Br:21])=[CH:20][C:11]2=3)[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Br:21][C:19]1[CH:18]=[N:17][C:12]2[O:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:11]=2[CH:20]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ncc(Br)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ncc(Br)cc54)CC3)nc2N1
Yield: 40.6 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Intermediate 209) (2.0 mmol), (3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (356 mg, 2.0 mmol) and sodium cyanoborohydride (496 mg, 4 equiv) were reacted as described under Example 21 to give the product as an off-white solid 420 mg (41% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:12][C:11]([CH2:32][NH2:33])=[N:10]1>N1C=CC=CC=1>[CH3:8][N:9]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:20]=2)=[N:12][C:11]([CH2:32][NH:33][C:1](=[O:3])[CH3:2])=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: CC(=O)NCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of acetic anhydride (0.089 g) in dry pyridine (1 ml) was added dropwise to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (A) (0.31 g) at 5°. The solution was stirred at room temperature for 0.5 h, and the solvent was removed under reduced pressure to leave a yellow oil which was triturated with light petroleum b.p. 60°-80° to give the title compound as a white solid (0.27 g), m.p. 123°.