Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)=[O:6]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:2]=1.[C:15](Cl)(=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=1
Reactant: Nc1ccccc1Nc1cccnc1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: C(=C/c1nc2ccccc2n1-c1cccnc1)\c1ccccc1
Yield: 34 %

Procedure:
To a stirred suspension of N-(3-pyridyl)-o-phenylenediamine (0.93 g, 5 mmol; Kirsch, P.; Schoenleben-Janas, A.; Schirmer, R. H. Liebigs Ann. Org. Bioorg. Chem., 1995, 7, 1275) in xylene (60 ml) was added (E)-cinnamoyl chloride (0.83 g, 5 mmol). After stirring at the room temperature for 1h, the resulting mixture was heated to reflux removing water using a Dean-Stark apparatus for 11 h. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved into ethyl acetate (100 ml), washed consecutively with saturated aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was purified by column chromatography (silica gel, 165 g; n-hexane/ethyl acetate (3/2 to 1/1)) to give 0.77 g (34%) of brown solids. Recrystallization from isopropyl ether yielded 0.50 g of the titled compound as pink solids. MW: 297.36; mp: 118.0-118.5° C.; 1H-NMR (CDCl3) δ: 8.84 (1H, dd, J=4.8, 1.5 Hz), 8.79 (1H, d, J=2.6 Hz), 8.00 (1H, d, J=15.8 Hz), 7.88-7.79 (2H, m), 7.61 (1H dd, J=8.1, 4.8 Hz), 7.50-7.44 (2H, m), 7.39-7.15 (6H, m), 6.78 (1H, d, J=15.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2].[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[C:32]([CH:47]=[CH:48][CH:49]=1)[C:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32]3[CH:47]=[CH:48][CH:49]=[C:30]([O:29][CH3:28])[C:31]=3[O:50][CH3:51])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2]
Reactant: O=C(NCCN1C(=O)c2ccc(C(=O)O)cc2C1=O)OCCCCCCO
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cccc(C(OCCCCCCOC(=O)NCCN2C(=O)c3ccc(C(=O)O)cc3C2=O)(c2ccccc2)c2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an argon atmosphere, 1.02 g (2.70 mmol) of 1-[(4-carboxyphthalimidylethyl)aminocarbonyl]oxy-6-hexanol (compound 3a) was dissolved in 27 ml of pyridine. To the solution, 915 mg (2.70 mmol) of dimethoxytrityl chloride was added, and the mixture was stirred at room temperature. After 2 hours, 440 mg (1.30 mmol) of dimethoxytrityl chloride was further added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hours. 5 ml of ethanol was added to the reaction solution, and the mixture was then concentrated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The solution was washed with 50 ml of water twice and 50 ml of saturated saline once and dried over sodium sulfate. The solution was concentrated under reduced pressure, followed by azeotropy with 5 ml of toluene. The residue was purified by silica gel column chromatography (elution solvent: ethanol-chloroform, containing 0.3% pyridine) to obtain 1.88 g (pyridine salt, yield: 92%) of the title compound (compound 4a) as a yellow foam.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: C1COCCN1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCOCC1)C2

Procedure:
The title compound was prepared (0.09 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and morpholine (0.58 g, 6.76 mmol). mp 228-230° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8](=[N:11][NH2:12])[NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cccc(C#N)n1
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(N)=NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
11.97 g (101.4 mmol) 6-methylpyridine-2-carbonitrile are dissolved in 25 mL ethanol. After addition of 36.3 mL (304.05 mmol) hydrazine hydrate (w=30%) the reaction mixture is stirred for 24 hours at room temperature. The precipitated product (K1=1.45 g) has been filtered off and the filtrate is evaporated to ⅓ of its volume. After dilution with water the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine and dried (Na2SO4). The solvent has been removed yielding a K2 (11.11 g) of the desired product. The overall yield is 78.9%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 55 °C

Procedure:
To a stirred solution of 34.14 g (0.200 moles) of 4-bromoaniline in 130 ml toluene under N2, 18.00 g (0.220 moles) of diketene was added dropwise over a 10 minute period followed by 15 ml of toluene. The temperature rose to 80° C. during the addition; the solution was then refluxed 20 minutes, cooled to 55° C. and 60 ml of petroleum ether added. An immediate precipitation occurred. The tan-white crystals were filtered and washed with three 100 ml portions of 1:1 toluene/petroleum ether. The product was taken up in hot absolute ethanol and crystallisation induced by addition of toluene to the ethanolic solution. Three crops of crystals from the ethanol/toluene solvent system gave 22.90 g (43%) and had Rf 0.69 on silica TLC with ethyl acetate; mp 135.8°-137.2° C. Anal. Calcd. for C10H10BrNO2 : C, 46.90; H, 3.94; N, 5.47; Br, 31.20. Found: C, 47.13; H, 4.00; N, 5.46; Br, 31.31.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:15]=[CH:16]N(C)C)=[S:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[S:14][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH3:21])=[CH:16][N:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CN(C)C=NC(=S)NCCCCNC(=O)OC(C)(C)C
Product: Cc1ccccc1C(=O)c1cnc(NCCCCNC(=O)OC(C)(C)C)s1
Yield: 69 %

Procedure:
The title compound was synthesised from [4-(3-Dimethylaminomethylene-thioureido)-butyl]-carbamic acid tert-butyl ester and 2-methyl phenacylbromide (Literature: WO9907666) according to the procedure described for Example 25 in 69% yield. MS (m/e): 390.2 (MH+, 100%).
Reaction SMILES: O[C:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][CH2:4]1.Cl>C(O)C>[C:14]1([C:2](=[C:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(OC)cc2)CC1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reaction time: 18 h
Yield: 25 %

Procedure:
A mixture of 106 parts of ethyl 4-[hydroxy(4-methoxyphenyl)-phenylmethyl]-1-piperidinecarboxylate, 1200 parts of concentrate hydrochloric acid and 200 parts of ethanol was stirred and refluxed for 18 hours. Gazeous hydrogen chloride was bubbled through the mixture and stirring was continued for 18 hours at reflux temperature. The whole was evaporated. The residue was dissolved in a mixture of 200 parts of ethanol and 1950 parts of a hydrobromic acid solution 48% in water. The mixture was stirred and refluxed overnight. After evaporating, the residue was suspended in 1000 parts of water and treated with ammonium hydroxide. The oil was dissolved in 2100 parts of trichloromethane. The solution was washed with 500 parts of water, dried, filtered and evaporated. The residue was suspended three times in 70 parts of 2,2'-oxybispropane and the latter was evaporated each time. The residue was solidified in 40 parts of acetonitrile. The product was filtered off and dried, yielding 20 parts (25%) of 4-[phenyl(4-piperidinylidene)methyl]phenol; mp.>260° C. (intermediate 32).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: [H][H]
Reactant: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 94.5 %

Procedure:
1.42 g (3.1 mmoles) of Z-Glp-Nva-Pro-NH2 are dissolved in 30 ml of methanol. 0.2 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated, and the amorphous, solid residue is triturated with ether. The resulting crude product is dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.95 g (94%) of Glp-Nva-Pro-NH2 are obtained; Rf4 =0.36, [α]D25 =-87.0° (c=1%, in acetic acid). Amino acid analysis: Glu: 0.97 (1.0), Nva: 1.09 (1.0), Pro: 1.00 (1.0).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].O.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a cooled (−5° C.) solution of 3,4,5-trifluorobenzaldehyde (7.0 g, 43.75 mmol) in a mixture (50 ml, 9:1) of THF and water NaBH4 (1.662 g, 43.75 mmol) was slowly added in portions over a period of 30 min. The reaction mixture was allowed to attain room temperature over a period of 2 h and carefully poured into ice-cold dil HCl (200 ml, IN). The oily layer was extracted into CH2Cl2 (250 ml) and the organic layer washed with water (200 ml), dried (MgSO4) and evaporated. The crude product (7.08 g, quantitative) obtained was taken forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13]O)=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2
Reactant: ON=Cc1ccc(Br)c2cncnc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Br)c2cncnc12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 59.8 %

Procedure:
To a solution of 5-Bromo-quinazoline-8-carbaldehyde oxime (3000.00 mg; 11.90 mmol; 1.00 eq.) in DMF (15 ml) was added 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (10.42 ml; 17.85 mmol; 1.50 eq.) 50% in DMF. The resulting mixture was stirred at 100° C. for 45 min, LCMS showed major peak (MS: 252/254, 234/236) and small (MS: 208/209). The reaction mixture was cooled, poured into water, extracted with EtOAc, dried and concentrated to yield sticky solid, which was washed with ether to collected the title product (1665 mg. yield 59.6%). LC-MS (232/234 and 250/252).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:21][CH:2]=[N:1][C:3]=2[CH3:4])=[CH:18][C:17]=1[F:24]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncoc1-c1ccc(Cl)c(F)c1
Yield: 85.7 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.56 g, 7.44 mmol), 4-chloro-3-fluorobenzaldehyde (1.18 g, 7.44 mmol), and K2CO3 (2.06 g, 14.9 mmol) in MeOH (35 mL) was heated to reflux. After 1.5 hr water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. Chromatography on silica gel (Analogix® SF25-40G, 0%-30% EtOAc/hexanes, 30 mL/min) afforded 1.35 g (86%) of the title compound as a yellow solid. 1H NMR (300 MHz, CH3OH-d4) δ 8.18 (s, 1H), 7.62-7.55 (m, 1H), 7.52 (dd, J=1.9, 10.3, 1H), 7.49-7.44 (m, 1H), 2.42 (s, 3H). MS (DCI+) m/z 212 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([N:24]=[N+:25]=[N-:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:27].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:27])[C@@H:10]([N:24]=[N+:25]=[N-:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2N=[N+]=[N-])cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@@H](N=[N+]=[N-])C1

Procedure:
38.2 A solution of 440 mg (3S,4S)-3-azido-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 8.6 ml 1M tetrabutylammonium fluoride solution in THF was stirred overnight at r.t. The reaction mixture was concentrated. The crude product was isolated by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 1:1) to give 150 mg (3S,4R)-3-azido-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless liquid. MS 230 ([M])
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[C:15]([CH:21]=O)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:21][C:15]1[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCNC(=O)OC(C)(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (3-aminopropyl)-carbamic acid tert-butyl ester and 3,5-dimethylpyridine-2-carboxaldehyde in anhydrous MeOH with NaBH4 gave {3-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][N:9]=2)=[O:13])[C:18]=1[NH2:24]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (0.3 g, 1.17 mmol), 2,3-diamino-benzoic acid methyl ester Compound 8a (3.43 g, 20.64 mmol), HATU (7.85 g, 20.66 mmol), DIPEA (8.64 mL, 62 mmol) in DMF (250 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 90% of ethyl acetate in hexanes) to yield 2-amino-3-[(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-amino]-benzoic acid methyl ester Compound 8b (5.1 g, 63% yield) as a colorless gel. 1H NMR (300 MHz, CD3OD) δ 9.03 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.8 Hz), 3.49 (s, 3H); MS (ESI) m/z: 391 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].CCOCC.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(N(CC)CC)C>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:14]([N:13]([CH3:18])[CH3:12])(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(N)CN
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 30.7 g (0.35 mol) of 1,2-diamino-2-methylpropane, 150 ml of ether and 50 ml of triethylamine was cooled to 0° C. and 20 g (0.14 mol) of dimethylsulfamoyl chloride was added slowly. The reaction mixture was stirred for 30 minutes and evaporated to dryness. The residue was mixed with water, basified with K2CO3 and evaporated to dryness. Acetone was added and the mixture was filtered. Evaporation of the filtrate gave a solid which was recrystalized from toluene to give 16.5 g (60.3%) of product, mp 77°-78° C. The NMR and IR were consistent with the assigned structure.
Reaction SMILES: Cl[CH:2](Cl)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)O.[NH2:17][C:18]([NH2:20])=[S:19].[OH-].[K+]>CO>[F:13][C:12]([F:15])([F:14])[O:11][C:7]1[CH:6]=[C:5]([C:3]2[S:19][C:18]([NH2:20])=[N:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: OC(c1cccc(OC(F)(F)F)c1)C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(-c2cccc(OC(F)(F)F)c2)s1
Temperature: 50 °C

Procedure:
19-7 (0.182 g, 0.662 mmol) and thiourea (0.050 g, 0.662 mmol) were dissolved in methanol. Solid potassium hydroxide (0.037 g, 0.662 mmol) was then added and warmed to 50° C. while stirring under N2. Additional solid potassium hydroxide pellets were added until the reaction was complete. The reaction was then directly loaded onto a C18 preparative HPLC column. The titled compound was isolated upon evaporation. H1 NMR (DMSO): 7.75 ppm (s, 1H); 7.51 ppm (m, 3H); 7.26 ppm (d, 2H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(Sc2ccc(CO)cc2)cc1
Solvent: CCOCC
Product: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 183.9 %

Procedure:
To a stirred mixture of phosphorus tribromide (1.20 g, 4.43 mM) and dry ether (100 ml) was added a solution (20 ml) of 4-(4-methylthiophenoxy)benzyl alcohol (3.00 g, 12.1 mM) in dry ether at the room temperature, and the mixture was stirred for 12 h at the same temperature. The mixture was poured into ice water, and the mixture was extracted with ether. The extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with magnesium sulfate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzyl bromide (2.39 g, 64%) as colorless crystals, m.p.32.9° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2cccc(OCc3ccccc3)c2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4c(OCc5ccccc5)cccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Sodium hydride (36 mg, 1.5 mmol) was added in portions to a solution of 7-benzyloxyoxindole (360 mg, 1.5 mmol) in THF (8 ml), the mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (204 mg, 0.6 mmol), (prepared as described for the starting material in Example 5), in THF (4 ml) and DMF (1.5 ml) was added. The mixture was stirred for 30 minutes at ambient temperature followed by 1.5 hours at 65° C. The THF was removed by evaporation, the mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with water, ethyl acetate, and ether, and dried under vacuum to give 4-(7-benzyloxyoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (190 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.[CH3:17][NH:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[N:18]([CH3:17])[N:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CNN
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Solvent: OCCO
Product: COc1cccc(-c2nn(C)c3ccsc23)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.9 %

Procedure:
A mixture of 20 g of (3-bromothien-2-yl) (3-methoxyphenyl)methanone and 17 g of methyl hydrazine in 134 ml of ethylene glycol was stirred under nitrogen at 120°-130° C. The reaction was complete in 2.5 hours. The product was allowed to cool to room temperature, and thereafter quenched with water (200 ml) and extracted with ether (4×200 ml). The organics were dried over anhydrous magnesium sulfate and the solvents were evaporated to give an oil. The oil was purified by HPLC (3:1 hexane/ethyl acetate). This yielded 9 g of a solid which was recrystallized from ether to give 8.2 g of crystals, mp 99°-101° C.