Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (90 mg, 90%), MS (ISP) m/z=402.5 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and dimethylcarbamic chloride.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=[O:16].[Na+].S(=O)(=O)(O)O>Cl.C(O)(=O)C>[OH:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)cc1O
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) suspended in 3 M hydrochloric acid (12.5 mL) and acetic acid (20 mL), an aqueous solution (20 mL) of sodium nitrite (0.69 g, 10 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to 10% aqueous sulfuric acid (30 mL) at 0° C., and the resulting reaction mixture was heated with reflux for 1 hour. The desired product was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and purified by silica gel column chromatography to give 1.04 g of the desired product as a white solid (yield 53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[CH2:33](O)[CH2:34][CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:36][CH2:35][CH2:34][CH2:33][O:8]2)[CH2:7]1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCCO3)c(C(C)C)c1
Temperature: 125 °C
Yield: 66.3 %

Procedure:
A flask was charged with 0.40 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (0.89 mmol, 1.0 equiv), 10 mL of argon-sparged toluene, 0.65 mL of 1,3-propanediol (8.9 mmol, 10 equiv) and 0.015 g of p-toluenesulfonic acid monohydrate (0.09 mmol, 0.1 equiv). The atmosphere was purged with argon and the reaction flask was equipped with a Dean-Stark trap and warmed in an oil bath at 125° C. for 20 h under argon atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and partitioned between toluene and water. The aqueous solution was back extracted once with toluene, the combined organic solution was washed once with water, dried over potassium carbonate and concentrated in vacuo. The unpurified material was purified by flash chromatography over silica gel with gradient elution using acetone/heptane mixtures. After concentration. 0.3 g (66% yield) of 8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane was isolated as a solid. 1H NMR (C6D6, 500 MHz) δ ppm 1.02 (d, 6H, J=10 Hz), 1.12 (d, 6H, J=7 Hz), 1.24 (d, 6H, J=7 Hz), 1.31-1.28 (pent, 2H, J=5.5 Hz), 1.42 (d, 6H, J=20 Hz), 1.45 (d, 6H, J=7 Hz), 2.13 (d, 2H, J=14.5 Hz), 2.25 (dd, 2H, J=14.5, 6 Hz), 2.80 (sept, 2H, J=7 Hz), 2.86 (sept, 1H, J=7 Hz), 3.48 (t, 2H, J=5.5 Hz), 3.72 (t, 2H, J=5.5 Hz), 7.01 (td, 1H, J=7.5, 1.5 Hz), 7.08 (br t, 1H, J=7.5 Hz), 7.24 (s, 2H), 7.26-7.24 (m, 1H), 7.89 (br d, 1H, J=8 Hz); 31P NMR (C6D6, 200 MHz) δ ppm −2.7 (br singlet).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C#CCCC(=O)OCC
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.4 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (60 mg, 0.315 mmol) and triethylamine (17.70 mL, 126 mmol), were added 2-iodopyridine (1.29 g, 6.30 mmol), and the Pd(PPh3)2Cl2 (202 mg, 0.315 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added ethyl pent-4-ynoate (790 mg, 6.30 mmol) in solution in 2 mL of triethylamine. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 25 g, DCM/MeOH: 98/2 as eluent) to afford 1.17 g of ethyl 5-(pyridin-2-yl)pent-4-ynoate (Yield: 78%) as brownish oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([C:34]3[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([N:25]2[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:23]([C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[O:22])=[N:24]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccc2)cn1
Reaction time: 0.7 h

Procedure:
At room temperature, trifluoroacetic acid (2.4 mL) was added to a solution of the above-mentioned 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-4-carboxylic acid tert-butyl ester (0.639 g) in methylene chloride (15 mL), followed by stirring of the mixture for 0.7 hours. The reaction solvent was removed under reduced pressure, and the residue was partitioned between chloroform and saturated aqueous sodium hydrogencarbonate. The aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (0.446 g, 89%).
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:16]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][C:6]([OH:5])=[CH:7][CH:8]=1)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=Cc1ccccc1)NNC(=O)c1ccc(O)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
To 100 ml of acetic acid were added 5.0 g of p-hydroxybenzoylhydrazine and 5.5 g of cinnamoyl chloride, and the mixture was stirred at 20° C for 3 hours. The reaction mixture was then poured into 2 liters of water, and the produced precipitate was collected and washed with water. The so obtained product was then recrystallized twice from acetic acid and dried under reduced pressure to yield 3.1 g of N-cinnamoyl-N'-(p-hydroxybenzoyl)hydrazine as white crystals, m.p. 263°-264.5° C. Analysis: Calculated for C16H14N2O3 : C, 68.08%; H, 5.00 %; N, 9.92%, Found: C, 68.15%; H, 4.87%; N, 9.98%.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][CH:24]=[CH:25][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:42]=[O:43]>C(Cl)(Cl)Cl>[CH:42]([C:24]1[S:23][C:6]2[N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)[C:2](=[O:1])[N:3]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:26])[C:5]=2[CH:25]=1)=[O:43]
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3ccsc32)cc1
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(C=O)sc32)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 4′-{[2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2 g), phosphorus oxychloride (30 mL) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.96 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=1>>[CH3:18][C:19]1[O:23][CH:22]=[C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])[CH:20]=1
Reactant: Cc1cc(C(=O)O)co1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1cc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)co1
Yield: 61.6 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.0 mg (0.090 mMol) 5-methylfuran-3-carboxylic acid, 7.9 mg (62%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:10]3[C:11]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:19][CH:20]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3cccs3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3cccs3)cc21
Reaction time: 0.01 h
Yield: 149 %

Procedure:
Tert-butyl (1-(4-(1-methyl-2-oxo-7-(thiophen-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.024 mmol) was dissolved in dichloromethane (1.5 ml). TFA (1 ml) was added at room temperature and the reaction mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (14 mg, 78% yield). LCMS (Method D): RT=0.781 min, M+1=393. 1H-NMR (500 MHz, CD3OD) δ 7.66 (1H, s), 7.53-7.49 (2H, dd), 7.48-7.44 (2H, dd), 7.42-7.39 (1H, dd), 7.01-7.97 (1H, dd), 6.97-6.95 (1H, dd), 4.97 (2H, s), 3.44 (3H, s), 2.84-2.74 (2H, m), 2.64-2.55 (2H, m), 2.31-2.21 (1H, m), 2.07-1.93 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](B(O)O)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2ccccc21

Procedure:
A solution of 2,4-dichloropyrimidine (2.42 g, 16 mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (3.89 g, 13 mmol) and sodium carbonate (5.03 g, 47 mmol) in acetonitrile/water (2:1, 60 mL) was degassed with argon, then tetrakis(triphenylphosphine)palladium (300 mg, 1.6 mol) was added. The resulting mixture was heated to reflux for 2 h while a white suspension formed. The precipitate was cooled and filtered through a CELITE™/Silica gel plug. The filter cake was washed with EtOAc, the organic layer separated, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole as a light-pink solid. The solid filtrate from the reaction mixture was dissolved in DCM, dried over Na2SO4, filtered, and combined with the previous batch of product. The collected solids were dissolved in DCM, the solvent was evaporated under reduced pressure and EtOAc was added to form a suspension, the product was filtered and washed with hexanes, to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole (2.0 g, 33% yield) as a light-pink solid. An additional 0.45 g of product was obtained from the mother liquors.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[C:14]([F:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=3[F:19])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]2)[C:6]([F:29])=[CH:5][C:4]=1[F:30]>C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[C:14]([F:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=3[F:19])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[C:6]([F:29])=[CH:5][C:4]=1[F:30]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(F)c(F)c32)c(F)cc1F
Yield: 93.8 %

Procedure:
To 2 ml of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 320 mg of ethyl 1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 3 hours with stirring, and allowed to cool. The precipitate was collected by filtration, and washed with ethanol to obtain 280 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CO
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: Cl
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
p-Methoxycinnamic acid was dissolved in refluxing methanol containing a catalytic amount of hydrogen chloride to form methyl p-methoxycinnamate. The yield of purified ester was 85%, m.p. 88°-89° (lit. 90°; Dictionary of Organic Compounds, II, Sir Ian Heilbron, ed., p. 600 (1946)): λmaxCCl4 3.32, 3.38 and 3.52 (CH1 --OCH3), 5.81 (C=O), 6.1 and 10.15 (CH-CH, trans), 7.95 and 8.5--8.6 (ester)μ. The NMR (δ) supported the expected structure: 6.13-7.78 (series of multiples, aromatic and vinyl), 3.86 (--CO2CH3), and 3.78 (Ar--O--CH3).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)([CH3:19])[CH3:18])[CH2:16][O:15]2)=[CH:10][CH:9]=1>C(O)CC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:15])([C:17]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)([CH3:18])[CH3:19])[CH2:16][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
3.6 g (0.052 mole) of 1,2,4-triazole are added to a solution of 0.11 g (0.047 mole) of sodium in 30 ml of n-propanol at room temperature, while stirring. The mixture is heated to the reflux temperature and a solution of 2-(4-chlorophenyl)-2-[2-(1,2,4-triazol-1-yl)prop-2-yl]-oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours and then cooled and poured onto water. The mixture is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; chloroform:methanol=9:1). 3.7 g (24.2% of theory) of 2-(4-chlorophenyl)-1,3-di-(1,2,4-triazol-1-yl)-3-methyl-2-butanol of melting point 114° C. are obtained.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH2:30][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ccc(Cl)nc2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(Cl)nc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 8 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-(6-chloropyridin-3-yl)piperidin-4-amine dihydrochloride (0.196 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified with preparative HPLC giving the title compound (0.022 g, 8%). 1H NMR (500 MHz, CDCl3): δ 7.92-7.87 (m, 1H), 7.55-7.48 (m, 2H), 7.48-7.41 (m, 3H), 7.13-7.03 (m, 2H), 5.24-5.18 (m, 1H), 3.45-3.35 (m, 2H), 3.13-3.01 (m, 1H), 2.39-2.29 (m, 2H), 1.82-1.71 (m, 2H), 1.73 (s, 9H), 1.52-1.40 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 145.8, 141.7, 138.0, 134.1, 131.8, 130.2, 129.0, 126.6, 125.3, 124.1, 107.5, 61.9, 49.8, 47.8, 32.0, 27.8; Mass Spectrum: M−H+ 475.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
1,2-Dibromoethane (725 mg, 4 mmol) was added by portions of 70 μl every 30 minutes to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml) heated at 35° C. The mixture was stirred for a further 30 minutes after the completion of the addition and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with petroleum ether/ether, the solid was collected by filtration and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:24][C:25]1[N:35]=[C:28]2[CH:29]=[CH:30][C:31]([CH2:33]Cl)=[CH:32][N:27]2[N:26]=1>CN(C=O)C>[Br:24][C:25]1[N:35]=[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:32][N:27]2[N:26]=1
Reactant: ClCc1ccc2nc(Br)nn2c1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (1.4 g, 6.09 mmol) in DMF, is added cesium carbonate (5.9 g, 18.1 mmol) and 2-bromo-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 6.09 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with ice cold water and extracted with EtOAc (2×200 mL). The organic extract is washed with brine (2×30 mL), dried over sodium sulphate, and concentrated. The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane to give the title compound as a yellow sticky oil (1.4 g, 54%). LCMS m/z 442 (M+H)+.