Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH:7]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)CNC(c1ccccc1)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N(CC(=O)OCC)C(c1ccccc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
(RS)-{[(4-Chloro-phenyl)-phenyl-methyl]-amino}-acetic acid ethyl ester (18 g, 59 mmol) was dissolved under nitrogen in DCM (1500 mL), N-ethyldiisopropylamine (12.2 mL, 71 mmol) was added, cooled in ice and treated with a solution of allyl chloroformate (6.4 mL, 71 mmol) in DCM (50 mL). Stirring at 20° C. was continued for 16 h. The solution was extracted with 1 M citric acid (200 mL) and 50% NaCl solution. The crude product was purified by chromatography on silica gel in heptane with a gradient of ethyl acetate from 0-50% in 60 min. One obtained 18.1 g (78%) of colorless oil. MS: m/z=388 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][C:11](Cl)=[CH:12][CH:13]=1.Cl.Cl.[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH:33][C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH2:44][NH:43][CH2:42][CH2:41]2)=[O:35]>C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH:33][C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH2:44][N:43]([C:11]1[N:10]=[C:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([Br:7])=[CH:13][CH:12]=1)[CH2:42][CH2:41]2)=[O:35]
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Br
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Cs2CO3 (4.1 g, 12.6 mmol) and 4A sieves were dried under high vacuum at 150° C. for 6 to 10 hours before the start of the reaction. After cooling to room temperature, compound 94A (0.736 g, 2.53 mmol) and compound 1B (1.62 g, 3 mmol) were transferred to the reaction vessel and the atmosphere was purged with nitrogen. 12 mL of anhydrous DMA were then added and the reaction was stirred at 120° C. for 12 hours. The cooled reaction mixture was then diluted with ethyl acetate and 10% citric acid. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Concentration afforded an orange film/foam. Purification on Flash Master (SiO2, ethyl acetate/petroleum ether 0:100 to 40:60) afforded a white solid (1.15 g, 80% yield): 1H NMR (300 MHz, DMSO-d6) δ ppm 12.84 (1H, s), 8.03 (1H, d), 7.77 (2H, m), 7.58 (1H, d), 7.40 (4H, m), 6.86 (1H, d), 4.92 (2H, s), 3.78 (2H, t), 3.01 (2H, t), 1.34 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:16]=2)=[C:9]([Cl:27])[CH:8]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:2]
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Yield: 76 %

Procedure:
[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (0.9 g, 2.1 mmol) was stirred with ethyl chloroformate (8 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with H2O, brine and dried over sodium sulphate, filtered and concentrated to give {[4-(3-sec-butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester. (0.8 g, 76% yield)
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(N)=O
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Yield: 71.9 %

Procedure:
67.56 g of methyl carbamate, 2.97 g of p-toluenesulfonic acid monohydrate and 108.06 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 160 mL of acetic acid to be suspended. After being dissolved by heating, 800 mL of toluene was added thereto and then the solution was refluxed with vigorous stirring. According to the same procedure as Example 1, 102.28 g of the objective compound was obtained (71.9% yield, Z:E=99.8:0.2).
Reaction SMILES: [C:1](=[N:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2]
Reactant: CC(C)=Nn1c(C)nc2cnc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cnc3ccccc3c2n1NC(C)C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
A solution of N-isopropylidene(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.82 g, 7.64 mmol) dissolved in 40 mL of MeOH was treated with NaBH4 (1.16 g, 30.6 mmol). After stirring for 18 h, the reaction was quenched with saturated NH4Cl solution and partitioned between CH2Cl2 and 2% Na2CO3 solution. The organic portion was washed with 2% Na2CO3 solution, H2O and brine and dried over Na2SO4. The resulting organic portion was filtered and concentrated under reduced pressure to give N-isopropyl(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.84 g) as a yellow foam.
Reaction SMILES: [CH3:1][C@@:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@@:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][NH:3]1
Reactant: COC(=O)[C@]1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@]1(C)CC(C)(C)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate 106D in CH2Cl2 (60 ml) was added TFA (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:20])=[N:24][CH:25]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccc(Cl)cn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 60 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-5-chloro-pyridine with a yield of 60% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)[C:15](F)=[N:16][CH:17]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:20]=2)[C:15]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:16][CH:17]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.67 h
Yield: 88 %

Procedure:
A stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 0.834 g, 5.87 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.8776 g, 3.91 mmol) in THF (50.0 mL, 610 mmol) was treated dropwise with LiHMDS (1.0 M in THF, 16.74 mL, 16.74 mmol) at −15° C. (ice-salt bath) and stirred for 40 min. The reaction was then quenched with water and saturated NH4Cl (aq) (25 mL each) and diluted with EtOAc (25 mL). Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Chromatographic purification of the residue (silica gel, 0% to 1% MeOH/DCM) followed by washing of the purified product with isopropanol gave 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.07 g, 3.44 mmol, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=2.54 Hz, 1H); 8.23 (d, J=2.54 Hz, 1H); 7.95 (d, J=1.96 Hz, 1H); 7.90 (d, J=12.13 Hz, 1H); 7.18 (dd, J=17.41, 8.41 Hz, 4H); 6.86 (t, J=8.12 Hz, 4H); 4.86 (s, 2H); 4.82 (s, 2H); 4.01 (s, 3H); 3.81 (s, 3H); 3.79 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH:19]([C:3]([O:7][CH2:8][CH3:9])=[O:10])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1c(F)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cccc1Cl
Yield: 87.7 %

Procedure:
Into a mixture of 7.2 g of sodium hydride (60% in oil), 17.0 g of diethyl carbonate and 150 ml of tetrahydrofuran, 26.0 g of ethyl 2-chloro-6-fluorophenylacetate were added dropwise under heating, and then refluxed under heating for 8 hours. The reaction mixture was cooled, poured into iced dil. hydrochloric acid and extracted with t-butyl methyl ether. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30.4 g of diethyl (2-chloro-6-fluorophenyl)malonate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:18]=[C:5]1[CH:4]=[CH:3][C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:7][N:6]1[CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)NCCn1cc(Br)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCn1cc(-c2cccs2)ccc1=O
Temperature: 85 °C

Procedure:
A suspension of tert-butyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)ethylcarbamate (166 mg, 523 μmol), 2-thiopheneboronic acid (134 mg, 1047 μmol), Na2CO3 (785 μl, 1570 μmol) [2M], and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (31 mg, 42 μmol) in DME (2 mL) was heated to 85° C. for 45 min. The mixture was partitioned between CH2Cl2 and 10% Na2CO3 and the aqueous was extracted with CH2Cl2 (10 mL). The combined organics were dried over MgSO4 and purified on silica (12 g) eluting with 0>50% of 5% MeOH/CH2Cl2, and isolated as orange crystals from ACN. MS (ESI pos. ion) m/z (MH+): 321 (MH+). Calc'd exact mass for C16H20N2O3S: 320. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.42 (s, 9H) 3.51 (q, J=6.00 Hz, 2H) 4.14 (t, J=5.67 Hz, 2H) 4.96 (br. s., 1H) 6.63 (d, J=9.39 Hz, 1H) 7.01-7.09 (m, 2H) 7.23 (dd, J=4.99, 1.27 Hz, 1H) 7.47-7.51 (m, 1H) 7.61 (dd, J=9.39, 2.54 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1.[Br:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([S:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Br:17])[C:19]=2[CH3:28])(=[O:25])=[O:26])[CH:7]=1
Reactant: Cc1c(Br)cccc1S(=O)(=O)Cl
Reactant: COC(=O)CCc1c[nH]c2ccc(F)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)CCc1cn(S(=O)(=O)c2cccc(Br)c2C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
Into a flask, 3-(5-fluoro-1H-indol-3-yl)-propionic acid methyl ester (3, 530.000 mg, 2.39572E-3 mol), 3-bromo-2-methyl-benzene sulfonyl chloride (4, 710.33 mg, 0.0026353 mol), 62.35 mL methylene chloride, 17 mL 50% KOH and a catalytic amount of tetra-n-butyl ammonium hydrogen sulfate were combined and stirred at room temperature for 48 hours. The organic layer was washed with saturated sodium bicarbonate, dried over MgSO4 and filtered. The organic layer was concentrated at reduced pressure to afford a tannish solid. Purification by flash chromatography using a gradient of 0-25% ethyl acetate in hexanes over 35 minutes yielded the desired compound (5, 650 mg, 59.72%). 1H NMR consistent with desired compound. MS(ESI) [M+H+]+==454.0, 456.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:23][O:22][C:21]1[C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:17][CH:18]=[CH:19][N:20]=1
Reactant: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nccnc1NCC1CCNCC1
Reaction time: 0.5 h

Procedure:
4-[(3-Methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0015 mol) and trifluoroacetic acid (5 mL) were allowed to stir under nitrogen for 0.5 h. The reaction was concentrated in vacuo, and chromatographed on silica using methylene chloride/methanol/ammonium hydroxide (90/10/2) to give the title compound. M.S. (M+1): 223.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:20]2[CH:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[CH3:32][CH:33]([OH:43])[CH:34]([CH3:42])[O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(C(C)=O)C>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][CH2:5][CH2:4][N:39]3[CH2:40][CH2:41][CH:36]([O:35][CH:34]([CH3:42])[CH:33]([CH3:32])[OH:43])[CH2:37][CH2:38]3)[C:20]=2[CH:19]=1
Reactant: CC(O)C(C)OC1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CC(O)C(C)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 47.9 %

Procedure:
22.5 g (0.15 mole) of sodium iodide were added to a solution of 51.5 g (0.15 mole) of 10-(3-chloropropyl)-2-trifluoromethyl-phenothiazine in 400 ml of methyl ethyl ketone followed by the addition of 15.2 g (0.15 mole) of triethylamine and then 26 g (0.15 mole) of 1,2-dimethyl-2-(4-piperidyloxy)-ethanol. The mixture was then refluxed for 20 hours and after cooling, the precipitate formed was removed by vacuum filtration. The filtrate was evaporated to dryness and the oil residue was chromatographed over 1 kg of neutral alumina. Elution with ethyl acetate gave 34.5 g (48% yield) of 2-trifluoromethyl-10-[3-(4-[1,2-dimethyl-2-hydroxyethoxy]-piperidino)-propyl]-phenothiazine in the form of a clear amber oil.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[N:6][CH:5]=1)=[N+]=[N-].[H][H]>[Pd].[NH4+].[OH-]>[NH2:1][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc(C)cc1NC(=O)Nc1cncc(N=[N+]=[N-])n1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C)cc1NC(=O)Nc1cncc(N)n1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(6-azido-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (8 mg, 27 μmol) 95% EtOH (2mL) at room temperature was added concentrated NH4OH (10 μL) and 10% Pd on C (25 mg). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then held under 50 psi of hydrogen pressure and shaken on a Parr Shaker. After 2 hours the vacuum/purge cycle was repeated and the reaction held under hydrogen for another 2 hours. The suspension was then filtered through GF/F filter paper with EtOH and concentrated to a yellow film (3 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 6.83 (s, 2H), 3.95 (s, 3H), 2.33 (s, 3H). LRMS (ESI, Positive) m/e 274.2 (M+1).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([N+:22]([O-])=O)[C:8]([S:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][CH:10]=1.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:22][C:7]1[C:8]([S:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ncc(Cl)cc1N
Reaction time: 4.5 h
Yield: 85 %

Procedure:
To an ethanol solution (6 ml) of tert-butyl 2-[(5-chloro-3-nitropyridin-2-yl)thio]-2-methylpropanoate (442 mg) were added at room temperature acetic acid (6 ml) and iron powder (418 mg), followed by stirring for 4.5 hours. The reaction solution was diluted with ethyl acetate, followed by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added saturated sodium hydrogen carbonate and ethyl acetate, followed by filtration through Celite, and then the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 2-[(3-amino-5-chloropyridin-2-yl)thio]-2-methylpropanoate (342 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[OH-].[Na+]>Cl>[OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)O)c(O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A suspension of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2.0 g, 6.7 mmol) in 6N hydrochloric acid solution (10 mL) was heated and stirred at 100° C. for 1 hour. The solution was cooled to room temperature, made weakly acidic by the addition of an aqueous sodium hydroxide solution, and the resulting precipitate was collected by filtration. The crude crystals thus obtained were washed with water and dried to give the title compound (0.6 g, 33% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7](Cl)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:13]1([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:24]2[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[C:24]2[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Clc1cccc2c(Br)c(-c3ccccc3)cnc12
Product: Oc1cccc(-c2c(-c3ccccc3)cnc3c(-c4cccc(O)c4)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 1, substituting 4-bromo-8-chloro-3-phenyl-quinoline and 3-hydroxybenzeneboronic acid MS (ESI) m/z 390.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[C:29]([CH3:38])[CH:28]=1)[CH3:26].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[C:29]([CH3:38])[CH:28]=2)[CH3:26])=[O:12])=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(CN2CCCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)cc2CN2CCCCC2)ccc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 4.9 %

Procedure:
To a methylene dichloride (5.0 ml) solution of [4-tert-butyl-2-(piperidin-1-ylmethyl)phenoxy]acetic acid (111 mg) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (97 mg, 0.37 mmol), a portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (109 mg, 0.57 mmol), triethylamine (0.2 ml, 1.4 mmol), and catalytic amount of 4-(dimethylamino)pyridine were added at ambient temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was diluted with methylene dichloride and quenched with saturated aqueous solution of ammonium chloride. The organic layer was then washed with brine and dried over magnesium sulfate. After filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=40/1 to give oil which contained 4-(dimethylamino)pyridine. This crude product was purified by HPLC gradient from 0.05% aqueous solution of ammonium formate/acetonitrile=4/96 to 96/4 to furnish 9.1 mg (5% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH:17]([Sn])=[CH2:18]>C1(C)C=CC=CC=1.CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:17]=[CH2:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C[Sn]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Yield: 53.3 %

Procedure:
A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g of tetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t-butyl-4-methylphenol in 75 ml of toluene and 20 ml of N,N-dimethylformamide is treated with 13.06 g of vinyltin followed by heating at reflux for 4 hours. The reaction mixture is cooled and concentrated in vacuo. The residue is diluted with hexanes and filtered. The filter cake is washed with hexanes and the remaining tacky solid dissolved in 100 ml of chloroform-methanol (8:2) and purified by chromatography on silica gel with 1:3 ethyl acetate-hexanes to afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC 229(MH+).