Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:28])=O>C1C=CC=CC=1>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([Cl:28])=[O:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1

Procedure:
A solution of 10.0 g. p-tetradecyloxyphenylacetic acid in 100 ml. absolute benzene is treated with 19.9 g thionylchloride and refluxed for 2.5 hours. The reaction mixture is then evaporated under vacuum (i.v.) and azeotroped several times with benzene to remove residual thionylchloride, to obtain crude p-tetradecyloxyphenylacetylchloride, which may be used in Step E, below, without further refining.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([CH2:23][CH2:24][O:25][CH3:26])[CH2:14][CH:13]2[C:27]([O:29]C)=[O:28])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([CH2:23][CH2:24][O:25][CH3:26])[CH2:14][CH:13]2[C:27]([OH:29])=[O:28])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCN1CC(C(=O)O)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 3.0 ml of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1 N HCl. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 164°-165° C.; Mass spectrum (ES) 421.4 (M+H). Anal. for C20H24N2O6S: Calc'd: C, 57.1; H, 5.8; N, 6.7; Found: C, 57.3; H, 5.7; N, 6.4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.Cl.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C.CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: NCCCBr
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cc(NCCCBr)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (10 g, 54.5 mmol) in acetonitrile (200 mL) was added triethylamine (22.80 mL, 164 mmol) at 0° C., stirred for 5 min at r.t., and then added dropwise a solution of 3-bromopropan-1-amine hydrochloride (12 g, 68.8 mmol) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred for 1 h at r.t., filtered, and concentrated. Purification via FC afforded the title compound (5.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:15]1[CH2:16][CH2:17][C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:14]1=[O:19]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CCCC1
Product: O=C1C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)CCC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 5.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.0 g of cyclopentanone. Yield 4.4 g (78%), m.p. 300° C. (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].[CH:21]1[C:26]([CH:27]=O)=[CH:25][C:24]2[O:29][CH2:30][O:31][C:23]=2[CH:22]=1.N>>[O:31]1[C:23]2[CH:22]=[CH:21][C:26]([CH2:27][N:18]3[CH2:19][CH2:20][CH:15]([NH:14][C:6]4[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=5)[O:9][C:8](=[O:13])[CH:7]=4)[CH2:16][CH2:17]3)=[CH:25][C:24]=2[O:29][CH2:30]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: N
Product: CCc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1

Procedure:
Prepared from 6-Ethyl-4-(piperidin-4-ylamino)-chromen-2-one and piperonal in a manner analogous to that described above. 1H NMR (300 MHz, MeOD-d4) δ ppm 1.28 (t, J=7.63 Hz, 3H) 1.92 (m, 2H) 2.34 (m, 2H) 2.74 (q, J=7.46 Hz, 2H) 3.22 (m, 2H) 3.60 (m, 2H) 3.86 (m, 1H) 4.26 (s, 2H) 5.40 (s, 1H) 6.04 (s, 2H) 6.94 (m, 2H) 7.01 (m, 2H) 7.25 (m, 1H) 7.48 (m, 1H) 7.86 (s, 1H); MS (DCI/NH3) m/z 407 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.C(Cl)Cl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH:7][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:4]1
Reactant: NC1CC(F)(F)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CC(F)(F)C1
Reaction time: 16 h

Procedure:
0.60 g 3,3-Difluoro-cyclobutylamine hydrochloride were suspended using 40 ml CH2Cl2 and 2.9 ml of triethylamine added at ambient temperature while receiving a clear solution. Thereafter, 1.0 ml of methanesulfonylchloride were added dropwise at ambient temperature and the mixture left at that temperature for 16 h. The volatiles were removed in vacuo, the residue was redissolved using 200 ml of EE and 100 ml of a saturated aqueous Na2CO3-solution and the layers separated. The organic layer was washed twice using 20 ml of a saturated aqueous NaHSO4-solution each time and washed twice using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 700 mg of a colorless resin.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=3[Cl:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:13]=3[Cl:19])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1cc(N2CCCC2)ccc1OC12CC3CC(CC(C3)C1)C2

Procedure:
1.7 g. (0.00612 Mole) of 4-(1-adamantyloxy)-3-chloroaniline. 1.32 g. (0.00612 mole) of 1,4-dibromobutane and 1.86 g. (0.0135 mole) of potassium carbonate were combined in 50 ml. of absolute ethanol and refluxed for 18 hours.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]([OH:15])=O.[CH2:16]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:17].CO>O1CCCC1>[CH:24]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:13]=1[OH:15])[CH2:20][CH2:19][NH:18][CH2:16][CH3:17])=[O:27]
Reactant: CCNCCc1ccc(O)cc1
Reactant: O=CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCc1ccc(O)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (326 mmole, 52.81 g) in tetrahydrofuran (164 ml) cooled to 0° C., was added dropwise 96% formic acid (326 mmole, 14.99 g) over a 26 minute period. Reaction stirred at 0° C. for 30 minutes then a light suspension of N-ethyl-p-hydroxyphenethylamine (102 mmole, 16.88 g) in tetrahydrofuran (66 ml) was added over a 10 minute period. Reaction then stirred at 22° C. for 170 minutes before being treated with methanol (10 ml). After stirring for 90 minutes, reaction was concentrated in vacuo to an oil containing crystals. The mixture was taken up into methylene chloride and subjected to preparatory chromatography eluting with a gradient of 0 to 5% methanol methylene chloride over a thirty-minute period. The fractions containing the title compound were combined, concentrated in vacuo to afford 13.46 g of an oil that slowly crystallizes out. Fractions containing title compound and impurities were resubjected to preparatory column chromatography under the same conditions described above to afford an additional 2.61 g of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH:23][N:22]=3)[C:17]([Cl:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.O.CC(=O)OCC>C(Cl)Cl>[C:26]([C:24]1[NH:23][N:22]=[C:21]([NH:20][C:18]2[C:17]([Cl:30])=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:19]=2)[CH:25]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C(C)(C)C)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Nc2nc(-c3ccc(S(N)(=O)=O)s3)ncc2Cl)n[nH]1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of N-tert-butyl-5-(4-(5-tert-butyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophene-2-sulfonamide (95 mg, 0.22 mmol) and BCl3 (4 mL of 1N solution in DCM) in DCM (8 mL) was stirred for 0.5 h, After addition of water and extraction with EA (3×), the combined organic layers were dried (NaHSO4), filtered. The filtrate was concentrated to afford the title compound 5-(4-(5-tert-butyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophene-2-sulfonamide (C-236) (50 mg, 62%). LC-MS (m/z)=413 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 1.34 (s, 9H), 6.57 (s, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.81 (s, 2H), 8.47 (s, 1H), 9.52 (s, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([C@@H:33]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([O:56]COCC[Si](C)(C)C)([C:52]([F:55])([F:54])[F:53])[C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([C@@H:33]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([OH:56])([C:52]([F:53])([F:54])[F:55])[C:48]([F:49])([F:50])[F:51])=[CH:43][CH:42]=3)[CH2:34][C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)[CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(OCOCC[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)cc2)cc1OC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1OC1CCCC1
Yield: 87.4 %

Procedure:
Tetrabutylammonium fluoride (1.0M in THF; 30.4 mL, 30.4 mmol) was added dropwise to a solution of (R)-4-{2-(3-cyclopentyloxy4-methoxyphenyl)-2-[4-(2-(2-(trimethylsilyl)ethoxymethoxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]ethyl}pyridine from Step 4 (4.08 g, 6.09 mmol) in THF (50 mL) at room temperature, and the resulting solution was heated to the reflux temperature for 2.5 h, allowed to cool, and 25% aqueous NH4OAc buffer was added. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed successively with 25% aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane 1:1) to afford a white solid subsequently triturated in 1:4 Et2O/hexane to give the title compound (2.87 g, 87%). 1H NMR (400 MHz, acetone-d6) δ 1.50-1.62 (m, 2H), 1.63-1.88 (m, 6H), 3.44 (m, 2H), 3.71 (s, 3H), 4.43 (t, J=8 Hz, 1H), 4.75 (m, 1H), 6.81 (m, 2H), 6.89 (s, 1H), 7.14 (d, J=6 Hz, 2H), 7.44 (s, 1H), 7.51 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 8.33 (d, J=6 Hz, 2H).
Reaction SMILES: [Sb+]=O.[CH2:3]([P:5]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])[O:6][CH2:7][CH2:8][OH:9])[CH3:4].[C:15]([OH:26])(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.[P:27]([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C(O)CO>[C:15]([OH:26])(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.[CH2:3]([P:5]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])[O:6][CH2:7][CH2:8][OH:9])[CH3:4].[P:27]
Reactant: O=P([O-])([O-])[O-]
Agent: CC(=O)[O-]
Agent: CCP(=O)(CCCO)OCCO
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: OCCO
Product: [P]
Temperature: 200 °C
Yield: 0.9 %

Procedure:
Terephthalic acid, ethylene glycol and 2-hydroxyethyl ethyl(3-hydroxy-propyl)phosphinate (produced as in Example 11) are polymerized in a weight ratio of 1000:650:70 in the presence of zinc acetate and antimony(III) oxide under the usual conditions. To 19.6 g of 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate are added 290 g of terephthalic acid, 188 g of ethylene glycol and 0.34 g of zinc acetate, and the mixture is heated to 200° C. for 2 h. Then, 0.29 g of trisodium phosphate anhydrate and 0.14 g of antimony(III) oxide are added, followed by heating to 280° C. and subsequent evacuation. The melt obtained (351 g, phosphorus content 0.9%) is used to injection mold test specimens 1.6 mm in thickness for measurement of the limiting oxygen index (LOI) to ISO 4589-2 and also for the UL 94 (Underwriter Laboratories) flammability test. The test specimens thus produced gave an LOI of 40% O2 and were UL 94 classified as flammability class V-0. Corresponding test specimens without 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate gave an LOI of just 31% O2 and were UL 94 classified as flammability class V-2 only. The polyester molded article containing 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate hence clearly has flame-retardant properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][C:18]([O:24]C)=[C:19]([O:22]C)[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+].[BrH:35]>C(O)(=O)C.C(N(CC)CC)C.CC(C)=O>[BrH:35].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:24])=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]3[CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: CCI
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN1CCc2cc(O)c(O)cc2C1C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (7.29 g prepared as described in Example 50), ethyl iodide (1.76 ml), anhydrous potassium carbonate (5.52 g) and acetone (100 ml) was heated under reflux for 16 hours. The reaction mixture was filtered and the solvent was removed by evaporation to give a residue which was digested with a 9:1 mixture of petroleum ether and triethylamine. The solution was filtered and the solvent removed to give a residue. A sample of this residue (4 g) was heated under reflux in a nitrogen atmosphere with glacial acetic acid (40 ml) and 48% hydrobromic acid (40 ml) for 20 hours. Removal of the solvent gave a residue which was dried by azeotropic distillation with industrial methylated spirit, then with propan-2-ol and finally with a mixture of toluene and propan-2-ol to give a solid which was washed with propan-2-ol and dried in vacuo at 80° C. to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-ethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 213°-215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]2[C:6]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:21][CH2:22][CH3:23])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([O:21][C:11]1[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[CH:3]=[C:4]([O:24][CH3:25])[C:5]=3[C:6]=2[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]=1)[CH3:23]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)cc(OC)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(-c3ccncc3)cc(OC)c12

Procedure:
60 mg (0.15 mmol) 7-bromo-4-ethoxy-9-methoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole (Example 1), 47 mg (0.23 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 61 mg (0.45 mmol) K2CO3, 2.4 mg (6.0 μmol) S-Phos and 0.7 mg (3.0 μmol) Pd(OAc)2 in 6 ml dioxan were heated in a microwave oven to 120° C. for 1 h. Thereafter, the solvent was removed and following LC (CH2Cl2:MeOH, 0-30%) 27 mg (45%) of the title substance was obtained. ESI-MS [m/z]: 405 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[OH:47]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:39][C:40]3[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=3[OH:47])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: Cc1ccc(O)c(NC(=O)c2ccc(Oc3ccc(OCc4ccccc4)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
A solution of the product from Example 43D and 2-Amino-4-methyl-phenol was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(2-hydroxy-5-methyl-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (15 mg, 29%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 2.22 (s, 3 H) 3.29 (m, 1 H) 6.79 (m, 4 H) 6.92 (m, 3 H) 7.47 (d, J=1.32 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H) 7.97 (dd, J=8.46, 2.21 Hz, 1 H) 8.13 (d, J=2.21 Hz, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.45 (m, 3 H) 11.46 (s, 1 H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[C:8]([N:10]([C:48](=[O:50])[CH3:49])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:25]=[N:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:51][CH3:52])[N:5]=1)[CH3:3]>O1CCOCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([N:10]([C:48](=[O:50])[CH3:49])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:51][CH3:52])[N:5]=1)[CH3:3]
Reactant: CCc1cc(N(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)C(C)=O)cc(CC)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C(C)=O)cc(CC)n1
Reaction time: 4 h

Procedure:
4M Hydrochloric acid (1.5 ml) was added to a solution of 2,6-diethyl-4-[N-acetyl-N-(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (A) (0.67 g) in 1,4-dioxan (10 ml) and the mixture was stirred for 4 hours. Volatile material was removed by evaporation and the residue purified by flash chromatography eluting with dichloromethane/methanol (17:3 v/v) to give 2,6-diethyl-4-[N-acetyl-N-(2'-(1H-tetrazol-5-yl)biphenyl-4yl)methylamino]pyridine as a solid; NMR (d6 -DMSO): 1.17(t, 6H), 1.97(t, 3H), 2.67(q, 4H), 4.89(s, 2H), 6.95(s, 2H), 7.05(q, 4H), 7.55(m, 4H); mass spectrum (+ve FAB, benzyl alcohol/methanol): 449(M+Na)+, 427(M+H)+ ; microanalysis, found: C, 67.8; H, 6.4; N, 18.5%; C25H26N6O.0.125C4H10O requires: C, 67.5; H, 6.5; N, 18.9%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCN>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COc1ccccc1CCN
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.04 g, 4 mmol) and 2- (2-methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.9 g (66%) of the title product:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: NO
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1Cl
Yield: 77.6 %

Procedure:
To a stirred solution of 56.2 grams (0.40 mole) of 2-chlorobenzaldehyde and 55.6 grams (0.80 mole) of hydroxylamine hydrochloride in 225 ml of ethanol and 111 ml of water was added in portions over a 15 minute period a solution of 24.0 grams (0.60 mole) of sodium hydroxide in 24 ml of water. The addition caused a solid precipitate to form. The reaction mixture was heated to boiling, and water was added until the solid dissolved. Additional water was added until the solution became cloudy. The reaction mixture was allowed to cool, and as it cooled a crystalline solid formed. The solid, collected by filtration, was dissolved in methylene chloride, and the methylene chloride solution was dried with sodium sulfate. The filtrate was concentrated under reduced pressure to remove ethanol, yielding additional solid, which was collected by filtration. This solid, too, was dissolved in methylene chloride, and the solution was dried with sodium sulfate. The two methylene chloride solutions were filtered from the sodium sulfate and the filtrates combined and concentrated under reduced pressure to give a residual solid. The solid was recrystallized from ethanol-water to give 48.3 grams of 2-chlorobenzaldoxime; mp 73.5°-75.5° C. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([NH:46][C:47](=[O:50])[CH2:48][CH3:49])[CH:43]=[CH:44][CH:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[CH:45]=[CH:40][CH:41]=[C:42]([NH:46][C:47](=[O:50])[CH2:48][CH3:49])[CH:43]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCC(=O)Nc1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 33.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.12 g), N-(3-bromophenyl)propanamide (1.56 g) and tetrakis(triphenylphosphine)palladium(0) (0.133 g), the title compound (1.26 g) was obtained as a colorless amorphous powder.