Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([C:16]=1[O:17][CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1OC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC)c2ccccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 4.6 g (0.096 mole) of 50% sodium hydride/mineral oil in 100 ml of N,N-dimethylformamide under a nitrogen atmosphere was cooled in an ice bath. To the stirred mixture was added over 45 minutes, a solution of 19.5 g (0.089 mole) of 3-methoxy-1H-indole-2-carboxylic acid ethyl ester [A. Galun, A. Markus, and A. Kampf, J. Heterocyclic Chem., 16, 221 (1979)] in 50 ml of N,N-dimethylformamide. The mixture was stirred for an additional 30 minutes, and a solution of 11.6 ml (16.7 g; 0.098 mole) of benzyl bromide in 10 ml of N,N-dimethylformamide was added over 15 minutes. The ice bath was removed, the mixture was stirred for an additional 16 hours, and then added to 800 g of ice water. The crude ester intermediate was removed by extracting with dichloromethane (4×250 ml). The combined organic layers were back-washed with brine (3×500 ml), dried (anhydrous sodium sulfate), and evaporated to yield a crude residue of 3-methoxy-1(phenylmethyl)-1H-indole-2-carboxylic acid ethyl ester, plus a small amount of N,N-dimethylformamide.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[CH2:20]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
(S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid (121 g, 0.664 mol) (Wang et al. Tetrahedron Lett. 1998, 39, 5501) in absolute EtOH (2 L) was treated with potassium carbonate (184 g, 1.33 mol) and benzyl chloride 169 g, 1.34 mol). The mixture was heated at reflux overnight and concentrated to about half the volume under vacuum. Aqueous 5N NaOH (100 mL) was added, and the mixture was stirred at ambient temperature overnight and then concentrated. The residue was acidified with concentrated HCl. The yellow sold was collected by filtration and dried overnight under vacuum at 50° C. The crude product in isopropanol (1.8 L) was heated at reflux for about 30 minutes, cooled to ambient temperature, and stirred for about 16 hours. The slurry was filtered and dried under vacuum at 70° C. overnight to give the title compound as a white solid (137 g, 76%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC=C(OC)C=3)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:39][CH3:38])[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: COc1cccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)c1
Product: COc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 467 (1.77 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:9 and 1:6 as the eluent to afford the title compound.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:2]2[S:3][C:4]3[CH2:9][CH2:8][C:7]4[S:10][CH:11]=[CH:12][C:6]=4[C:5]=3[N:1]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc2c(s1)CCc1sccc1-2

Procedure:
The title compound was prepared from 4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-amine (106 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and 3-chloro-2-methylbenzenesulfonyl chloride (114mg) as described in the synthetic METHOD A to give a white powder (36 mg) with a purity >90%: MS-ES (neg) m/z 395.2.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([CH3:13])=[N:10][C:9]=1[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([O:26][CH2:27]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([C:8]1[N:12]([CH2:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([CH3:13])=[N:10][C:9]=1[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(C)C)c(Cc2ccccc2)[nH]1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)c(Cc2ccccc2)n1COCc1ccccc1
Yield: 53.5 %

Procedure:
To a solution of 980 mg of 5-benzyl-4-isopropyl-2-methylimidazole (4.58 mmol) in 9.8 ml of dry dimethylformamide is added 238 mg of 60% oil suspension of sodium hydride (5.95 mmol) under ice cooling. Ten minutes later, 935 mg of benzyloxymethyl chloride (5.97 mmol) is dropwise added. One hour later, the reaction mixture is poured onto ice water and extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the liltrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate and n-hexane (1:1) to give 820 mg of the objective 5-benzyl-1-benzyloxymethyl-4-isopropyl-2-methylimidazole (I-42). Yield, 54.17%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:24]1([CH2:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: NCC1CCCCC1
Product: COc1ccc(CN(CC2CCCCC2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and cyclohexylmethanamine. MS (M−H, 416.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 0.63 (m, 2H), 0.87 (m, 3H), 0.94 (m, 1H), 1.25-1.52 (m, 5H), 1.70 (m, 2H), 2.86 (m, 2H), 3.70 (s, 3H), 4.22 (s, 2H), 6.84 (m, 2H), 7.16 (m, 2H), 7.91 (m, 2H), 7.62 (m, 2H), 8.09 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:19]/[C:15]1[NH:14][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 18.2 %

Procedure:
Methyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (37 mg, 0.39 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of methyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate as a yellow solid. MS(ES): m/e 275 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5](=[CH:26][CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[N:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH:39]=O.N1C=CC=CC=1.N1C=CC=CC1>C(#N)C>[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[C:39]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(=CC=Cc1ccc(Cl)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1=CCNC=C1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
The residue of 3-methoxycarbonyl-6-(4-chlorophenyl)-1,1,1-triphenyl-2-aza-1λ5-phosphahexa-1,3,5-triene (10.2 mmol) from Step D was dissolved in acetonitrile (40 mL) and 2,4-dichlorobenzaldehyde (1.78 g, 10.2 mmol) was added. The reaction was heated to 60° C. under a condenser (left open to the air) for 20 h. HPLC/MS indicated a mixture of the desired title pyridine and dihydropyridine intermediate 394 (M+1), 396 (M+3), Rt=4.75 min). The reaction was heated a further 4 h and was then concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0 to 20% ethyl acetate in hexanes to afford methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-2-carboxylate. HPLC/MS: 392 (M+1), 394 (M+3); Rt=4.16 min. 1HNMR (CDCl3): δ 4.039 (s, 3H), 7.09 (br d, J=8.5 Hz, 2H), 7.26 (br d, J=8.4 Hz, 2H), 7.28 (d, J=2 Hz, 1H), 7.30 (dd, J=2.0 and 8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)[CH:3]=1.[OH-].[Na+:41]>C1COCC1>[Na+:41].[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[C:22]([C:27]([O-:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:19][CH:20]=3)[C:6]=2[CH:5]=[C:4]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)[CH:3]=1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)[O-])cc1

Procedure:
10 g of telmisartan are suspended in 40 ml of THF in a round-bottom flask equipped with magnetic stirrer, condenser and under nitrogen atmosphere. The solution is added with 1.5 ml of 50% aq NaOH and the mixture is heated under reflux, then evaporated to a residue. 10.4 g of telmisartan sodium salt are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH3:22])[C:9]1[C:14]2[N:15]([CH3:19])[C:16](Cl)=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[NH2:31]>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:20][CH2:21][CH3:22])[C:9]1[C:14]2[N:15]([CH3:19])[C:16]([NH:31][C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[CH3:32])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(Cc1ccccc1)c1cccc2nc(Cl)n(C)c12
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCOC(C)=O
Product: CCCN(Cc1ccccc1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A solution of 0.56 g (1.8 mmol) of N7-benzyl-2-chloro-1-methyl-N7-propyl-1H-benzimidazol-7-amine in 0.75 mL (5.4 mmol) of mesityl amine was heated to 130° C. After stirring for 24 h, the mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give a tan solid. The solid thus obtained was purified by flash chromatography eluting with a 1.3% methanol/dichloromethane mixture to give 0.59 g (80%) of the title compound as a cream colored solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:11])=[O:10])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[CH:7]=2)[CH2:2]1)=[O:18]
Reactant: CN=C=O
Reactant: NC(=O)c1cccc(OC2CNC2)c1
Product: CNC(=O)N1CC(Oc2cccc(C(N)=O)c2)C1

Procedure:
The compound was prepared from 3-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 6 of U.S. Pat. No. 4,226,861, m.p. 238°-240° C.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][N:13]1[CH:17]=[C:16]([C:2]2[NH:7][C:6](=[O:8])[N:5]3[CH:9]=[CH:10][N:11]=[C:4]3[CH:3]=2)[CH:15]=[N:14]1
Reactant: O=c1[nH]c(Cl)cc2nccn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Product: Cn1cc(-c2cc3nccn3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a mixture of 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (Preparation H, 10.0 g, 59.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.0 g, 88.5 mmol) and XPHOS (2.81 g, 5.90 mmol) in isopropyl alcohol (400 mL) was added 2M K3PO4 (88.5 mL, 177 mmol). The mixture was purged with N2 for 15 minutes with vigorous mixing and Pd2dba3 (2.70 g, 2.95 mmol) was added. The mixture was heated at reflux under a N2 atmosphere for 20 hours. The mixture was charged additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.00 g) and Pd2dba3 (1.00 g) and heated at reflux for an additional 20 hours. The mixture was cooled to ambient temperature and concentrated to an aqueous syrup. The syrup was partitioned into H2O (500 mL) and 50% EtOAc-hexanes (250 mL) and mixed. The mixture was filtered through filter paper and the orange organic layer was removed. The aqueous layer was washed with 50% EtOAc/hexanes and was cooled on an ice bath. The solution was treated with concentrated HCl to pH 6 with stirring and the resulting fine precipitate was collected, washed with H2O and Et2O and dried under vacuum to provide the title compound (9.65 g, 76% yield) as faint grey solid. MS (apci) m/z=216.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=CC=CC=2)[CH:12]=[CH:11][CH:10]=1)[C:3](O)=[O:4].NC(CCOC1C=CC=CC=1)C(O)=O>>[NH2:1][CH:2]([CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: NC(CCOc1cccc2ccccc12)C(=O)O
Agent: NC(CCOc1ccccc1)C(=O)O
Product: NC(CO)CCOc1ccccc1

Procedure:
In the same manner but replacing 2-amino-4-(1-naphthyloxy)butanoic acid with an equivalent amount of 2-amino-4-phenoxy-butanoic acid, described by Y. Knobler, et al., J. Org. Chem., 24, 1794 (1959), 2-amino-4-phenoxy-1-butanol, γmaxCHCl3 3230-3400, is obtained. The hydrochloric acid addition salt of 2-amino-4-phenoxy-1-butanol has mp 136°-138° C., after recrystallization from methanol-diethyl ether.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[C:37]([CH3:43])([CH3:42])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN1CCNCC1(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1(C)C

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](O)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([Cl:20])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Reactant: O=S(Cl)Cl
Product: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (29.5 g) and thionyl chloride (18 ml) in dry doluene (900 ml) were stirred and heated under reflux for 1 hour. The solution was cooled and the solid that separated was collected. It had m.p. 186.5°-188.5° (98%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.[F:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[CH:23]=O.[S-2].[Na+].[Na+]>CO.O.Cl>[F:16][C:17]1[CH:18]=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[C:23]1[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1cccc(-c2ccc(C=O)c(F)c2)c1
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(-c2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(F)c2)c1
Temperature: 70 °C

Procedure:
A solution of 2,3-diaminobenzoic acid (0.15 g, 0.824 mmol) in methanol (2 mL) was acidified with acetic acid (0.5 mL) To this mixture was added a solution of 3-fluoro-3′-methoxy-biphenyl-4-carbaldehyde (0.2466 g, 1.0695 mmol) in methanol followed by a solution of cupric acetate (0.183 g, 0.919 mmol) in water (4 mL). The resulting mixture was stirred vigorously and heated to 70° C. for 5 minutes and then filtered hot. The precipitate was washed with water and dissolved in ethanol (5 mL) containing 0.5 mL conc. HCl. A solution of sodium sulphide (0.082 g, 1.0512 mmol) in water was added. The reaction mixture was kept acidic by adding 2-3 drops of conc HCl. The reaction mixture was filtered hot to remove copper sulfide. The pH of the solution adjusted to 4 and diluted with water. The precipitate formed was filtered, washed with water and dried. The residue obtained was purified by column chromatography using 5% methanol in dichloromethane to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](=S)[NH:12][C:11]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:11]=2[N:12]=1
Reactant: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 640.1 %

Procedure:
5-Phenyl-3H-benzooxazole-2-thione (227 mg, 1.0 mmol) was dissolved in phosphorus oxychloride (1.6 mL). Phosphorus pentachloride (208 mg, 1.0 mmol) was added and the mixture was placed in an oil bath at 100° C. for 3 h. The mixture was allowed to cool to RT and concentrated. The crude residue was concentrated from CH2Cl2 (3×). The crude reaction product was triturated with hexanes (40 mL), and the resulting solids were collected by filtration. The solids were washed with hexanes (20 mL×3) and dried to afford 1.47 g (73%) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, 1H, J=1.3 Hz), 7.60-7.56 (m, 3H), 7.55-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 151.6, 151.4, 141.9, 140.7, 139.3, 129.2, 127.8, 127.7, 125.2, 118.4, 110.7; MS (Cl) m/z 230.1 (M+1); HPLC retention time=5.41 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:27]=O)=[N:18][CH:19]=[C:20]([N:22]([CH3:26])[CH2:23][CH2:24][CH3:25])[N:21]=1.[CH2:29]([NH:36][CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:29]([N:36]([CH2:27][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH3:26])[CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=1)[CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCN(C)c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCN(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Sodium triacetoxyborohydride (0.74 g) was added to a solution of 3-chloro-5-[methyl(propyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.42 g) and acetic acid (0.40 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.75 g, 91%) as a pale-yellow oil.
Reaction SMILES: CC(O)=O.Cl[C:6]1[N:7]=[N:8][CH:9]=[C:10]([Cl:13])[C:11]=1[NH2:12].[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[Cl:13][C:10]1[C:11]([NH2:12])=[C:6]([NH:17][CH:14]([CH3:16])[CH3:15])[N:7]=[N:8][CH:9]=1
Reactant: Nc1c(Cl)cnnc1Cl
Reactant: CC(C)N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1nncc(Cl)c1N
Temperature: 0 °C
Yield: 74 %

Procedure:
HOAc (2.47 mL, 42.7 mmol) was added dropwise to a mixture of 3,5-dichloropyridazin-4-amine (Preparation 4, 1000 mg, 6.098 mmol) and isopropylamine (7.27 mL, 85.4 mmol) cooled to 0° C. The resulting solid/suspension was heated under microwave irradiation at 105° C. for 5 hours. The reaction mixture was dissolved in minimum amount of MeOH and purified by silica gel column chromatography eluting with EtOAc:heptane: 10%-90% to provide the title compound as a slightly brownish solid in 74% yield, 2.52 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][NH:34][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(=O)C)[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][NH:34][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cnn(C)c5c4)c4cc[nH]c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1ncc2ccc(Nc3nc(Nc4ccc(N5CCNCC5)cc4)nc4[nH]ccc34)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 14.5 %

Procedure:
To a solution of 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg, 0.047 mmol) in dioxane (2 mL), aq. 1N KOH (2 mL, 2.00 mmol) was added. The mixture was stirred at 70° C. for 3 h. HOAc (0.3 mL) was added. The mixture was purified by HPLC to give N4-(1-methyl-1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (3 mg), MS 440.3 (M+H) (Compound 22-1); and 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (7 mg), MS 482.3 (M+H) (Compound 22-2).