Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>>[F:12][CH:11]([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:20]3[CH:19]=[C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:17]=[CH:16][C:15]=3[F:14])=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2cc(-c3ccccc3C#N)ccc2F)OC1(C)C
Reactant: FC(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1ccc(F)c(-c2cnc3nc(C(F)F)ccn23)c1
Yield: 49 %

Procedure:
3-Bromo-7-difluoromethylimidazo[1,2-α]pyrimidine (124 mg, 0.50 mmol) was coupled with 4′-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-difluoromethylimidazo[1,2-α]pyrimidin-3-yl)-4′-fluorobiphenyl-2-carbonitrile (180 mg, 49%) as a yellow powder: δH (400 MHz, CDCl3) 6.69 (1H, t, J 55), 7.32 (1H, d, J 7), 7.42-7.57 (3H, m), 7.64-7.76 (3H, m), 7.84 (1H, dd, J 8 and 1), 8.13 (1H, d, J 1), 8.79 (1H, dd, J 7 and 2); m/z (ES+) 365 (M++H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](OC)[CH:11]=2)[NH:6][CH:5]=1.[F:15]C1C=C2C(=CC=1)NC=C2>>[Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[NH:6][CH:5]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Product: Fc1ccc2[nH]cc(CCBr)c2c1

Procedure:
The title compound was synthesized according to above mentioned procedure for 3-(2-bromoethyl)-5-methoxy-1H-indole, starting with 5-fluoroindole yielding a brown oil which was stored in the freezer. LC-MS conditions B: tR=0.82 min, [M(81Br)+MeCN+H]+=244.07.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2cc(OCCc3ccccc3)ccc21
Yield: 61.1 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (2.0 g, 12.3 mmol) and (2-bromoethyl)benzene (4.8 g, 25.8 mmol) in ACN (20 mL) was added potassium carbonate (3.4 g, 24.6 mmol) at rt. The solution was heated at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM=10:1:2) to give 2.0 g (61%) of the title compound as a brown oil. 1H NMR (300 MHz, CDCl3): δ 2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.92 (2H, t, J=6.3 Hz), 3.13 (2H, t, J=7.2 Hz), 2.92 (2H, t, J=7.2 Hz), 6.71 (1H, d, J=2.1 Hz), 6.83 (1H, dd, J=2.4, 8.7 Hz), 7.27-7.38 (5H, m), 8.01 (1H, dd, J=8.7 Hz).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]I.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: FC(F)CI
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 80.2 %

Procedure:
26.3 g (0.135 mol) of 2,2-difluoro-1-iodoethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. The mixture is heated to 100° C. for 50 minutes and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water. 3 ml of 45% sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene. The product is subsequently finely distilled under reduced pressure. This gives 11.1 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 79.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH2:18]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20](Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:20][CH2:18][C:11]1[C:12]([CH3:17])=[N:13][N:14]([CH2:15][CH3:16])[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCn1nc(C)c(CO)c1Sc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 460 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl-]methanol, 481 mg of carbon tetrabromide and 380 mg of triphenylphosphine in 20 ml of dichloromethane was stirred at room temperature for 24 hours. The solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) for the elution to give 392 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulfanyl)-1-ethyl-3-methyl-1H-pyrazole as a pale yellow oil. Mass spectrum (ES) m/z 317 [M−Br+H2O]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)=[O:20])=[N:16][NH:15][C:12]2=[N:13][N:14]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])=[N:16][NH:15][C:12]2=[N:13][N:14]=1
Reactant: O=C(Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12)C1CCNCC1

Procedure:
A mixture of 1-benzyl-piperidine-4-carboxylic acid [5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-amide (Example 209; 340 mg, 0.76 mmol), ammonium formate (191 mg, 3.03 mmol) and 10% Pd/C (50 mg) in ethanol (10 mL) was stirred at reflux for 72 h. The reaction mixture was cooled, filtered through celite and concentrated. The residue was purified by chromatography on silica gel using initially 10% v/v methanol in dichloromethane and rising to 10% v/v 2N methanolic ammonia in dichloromethane to afford the title compound, a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:27]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:28]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)C1CCCCC1
Yield: 45 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with cyclohexanecarbonyl chloride in 45% yield.
Reaction SMILES: N#N.[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][CH:10]=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl>O.ClC1C=CC=CC=1Cl>[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][C:10]([CH:28]=[O:31])=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1ccc2c(c1)ccc1c3ccccc3ccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reaction time: 4 h

Procedure:
A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser and N2 line was charged with chrysene (Eastman Kodak Co., Rochester, NY., 14650, 100 g, 0.438 mol) and o-dichlorobenzene (2.5 L). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich Chemical Co., Milwaukee, WI, 53201, 98%, 228.2 g, 0.876 mol, 102.4 mL) was added in one portion. No temperature change occurred. The reaction mixture was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 70.48 g, 0.613 mol, 55.45 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h, the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was split into 2 portions and each passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted chrysene (3 g) from the aldehyde and a nore polar product. Fractions containing the aldehyde were combined and the PhCH3 removed. Crystals formed during this process and were removed periodically by filtration. After drying (at 60°) the yield of 6-chrysenecarbaldehyde was 89.46 g (79.7%) mp 167°-169°, (C,H), (lit. 168°, N. P. Buu Hoi, J.-P. Hoffinger, and P. Jacquignon, Bull. Soc. Chim. Fr. 3808 (1968)).
Reaction SMILES: [H][H].CO.[ClH:5].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:15]([OH:17])[OH:16])([O-])=[O:7]>[Pd]>[ClH:5].[OH:7][NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:15]([OH:17])[OH:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: ONc1ccccc1B(O)O
Temperature: 24 °C

Procedure:
Into a Parr shaker hydrogenation apparatus fitted with a hydrogen source and Parr bomb was charged 0.1 gm of a palladium on carbon hydrogenation catalyst obtained from Aldrich Chemical Co. under the trade designation Palladium on Carbon, 100 mL of methanol containing 1 equivalent of hydrochloric acid, and 0.8 gm of 2-nitrophenyl-boronic acid prepared in accordance with the procedure described in W. Leaman and J. R. Johnson, J. Am. Chem. Soc., 1931, 53, 711. The apparatus was sealed and was flushed with hydrogen gas and maintained under 42 psi of hydrogen at a temperature of 24° C. for 4 hr. Solids were then removed by filtration, and the filtrate was vacuum concentrated. The tan, hygroscopic solid product (mp 185°-187° C. (dec)) was isolated by filtration:
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[SH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C>C1COCC1>[O:4]=[C:3]([CH3:5])[CH2:1][CH2:2][S:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCS
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCSCCC(C)=O
Reaction time: 4.5 h

Procedure:
Methyl vinyl ketone (90%, 185 ml, 2.0 mol) was added portionwise to a solution of methyl 3-mercaptopropionate (200 ml, 1.83 mol) and triethylamine (26 ml, 0.1 equiv) in THF (2.4 L). This mixture was heated slowly to 50 C and stirred at that temperature for 4.5 h. The solvent was then evaporated to afford 11 as an oil.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[I:18]CI.N(OCCC(C)C)=O>CC#N>[I:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17]
Reactant: ICI
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1ccc(-n2nc(C)c(C#N)c2I)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.30 g, 5.70 mmol) in MeCN (8 mL) was added diiodomethane (1.93 mL, 23.9 mmol) followed by isoamyl nitrite (0.19 mL, 1.42 mmol). The reaction vessel was heated using a heating gun to initiate the reaction. After the rest of isoamyl nitrite (1.72 mL, 12.8 mmol) was added and the reaction was stirred for 1 hour at 50° C. The reaction was concentrated into silica and purified using silica gel (Heptane-CH2Cl2 1:0 to 0:1) gave 5-iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.45 g, 75%).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14][N:13]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:10]2=[N:11][CH:12]=1)=[NH:6])C.[CH:30]([NH:32][NH2:33])=O.CCN(CC)CC>CCO>[C:24]1([S:21]([N:13]2[C:10]3=[N:11][CH:12]=[C:7]([C:5]4[NH:6][CH:30]=[N:32][N:33]=4)[CH:8]=[C:9]3[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14]2)(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NNC=O
Reactant: CCOC(=N)c1cnc2c(c1)c(-c1ccoc1)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3nnc[nH]3)cnc21
Temperature: 75 °C
Yield: 48.4 %

Procedure:
A mixture of 39 (300 mg, 0.70 mmol), formic hydrazide (209 mg, 3.47 mmol) and Et3N (759 μM, 6.95 mmol) in EtOH (10.4 mL) was heated at 75° C. overnight. After cooling, the solvent was evaporated and the residue purified by silicagel chromatography using 80% ethyl acetate in hexane (gradient elution) then preparative TLC (1 mm plates, EtOAc eluent) to give 40 as a white solid (132.6 mg, 76%); 1H NMR (400 MHz, CDCl3+2 drops CD3OD) δ 6.71 (m, 1H), 7.40-7.70 (m, 5H), 7.84 (s, 1H), 7.93 (t, J=1.0 Hz, 1H), 8.10-8.30 (m, 3H), 8.63 (d, J=2.0 Hz, 1H), 9.10 (bs, NH); MS (CI) m/z 391.9 (MH+), 433.1 (M+MeCN).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[ClH:20].[H][H]>O.[Pd]>[NH2:1][CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[CH:9]([CH3:17])[CH2:8]3.[ClH:20]
Reactant: [H][H]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CN)O3
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C(C)C3)OC(CN)C2C
Yield: 59.3 %

Procedure:
The trans compound obtained in Example 297 (380 mg, 1.29 mmol) was dissolved in water (30 ml). To the solution, 10% palladium-on-carbon (400 mg) was added. The mixture was stirred at 80° C. for 2 days in the stream of hydrogen. After removing the catalyst by filtration, the filtrate was distilled off under reduced pressure, and the residue was subjected to recrystallization from methanol-ether to obtain 227 mg of the title compound in a trans form as colorless crystals (59%). By a similar procedure using the cis compound obtained in Example 297 (165 mg, 0.56 mmol), 85 mg of the title compound in a cis form was obtained as colorless crystals (51%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]([NH:26][C:27]([NH:29][C:30]4[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[O:32][N:31]=4)=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[C:35]([C:33]1[O:32][N:31]=[C:30]([NH:29][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[N:16]=[CH:15][N:14]=3)[CH:21]=2)=[O:28])[CH:34]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCc5ccccc5)ccc34)c2)no1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(O)ccc34)c2)no1
Temperature: 85 °C
Yield: 60.1 %

Procedure:
1-(3-(7-(Benzyloxy)quinazolin-4-yloxy)phenyl)-3-(5-tert-butylisoxazol-3-yl)urea (725 mg, 1.42 mmol) was treated with trifluoroacetic acid (7 mL) and heated at 85° C. for 3h. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate/water. The solution was neutralized with saturated sodium bicarbonate (pH=8) and the organic layer separated. After extraction of the aqueous phase with ethyl acetate, the organic fractions were combined, dried (MgSO4) and concentrated under reduced pressure. The solid was triturated with ethyl acetate to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea (358 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.64 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.24 (d, 1H), 7.57 (s, 1H), 7.41 (t, 1H), 7.30 (d, 2H), 7.20 (s, 1H), 6.97 (d, 1H) 6.49 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C.[OH-].[Na+]>O1CCOCC1>[CH2:12]([NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1cc(Cl)nc(C(C)C)n1
Reactant: CCCCCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNc1cc(C)nc(C(C)C)n1
Temperature: 109 °C
Reaction time: 0.17 h

Procedure:
79.2 g of 4-chloro-2-isopropyl-6-methylpyrimidine (464.1 mmol) are heated in 100 ml of dioxane at 100° C. A heated solution of 189.3 g of dodecylamine (1021 mmol, 2.2 eq) in 30 ml of dioxane is added dropwise thereto over the course of 2 hours, and the reaction mixture is further heated for 2 hours at 100° C. and for 9 hours at 109° C. After cooling, 400 ml of ethyl acetate and 150 ml of 4M sodium hydroxide solution (600 mmol) are added thereto and the mixture is stirred at 50° C. for 10 minutes. The lower, aqueous phase is discarded, the organic phase is washed with 300 ml of water, and 10 ml of saturated NaCl solution are added thereto. The organic phase is separated off and concentrated, and the excess dodecylamine is distilled in vacuo up to a bath temperature of 160° C. 136.1 g (91.8%); GC purity: 98%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[S:5][C:6]=1Br.[Si]([O:20][CH2:21][CH2:22][CH2:23]I)(C(C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[S:5][C:6]=1[CH2:23][CH2:22][CH2:21][OH:20]
Reactant: Brc1cc(C2OCCO2)sc1Br
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Solvent: C1CCOC1
Product: OCCCc1sc(C2OCCO2)cc1Br
Temperature: -78 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
2-(4,5-Dibromo-2-thienyl)-1,3-dioxolane (for a synthesis, see J Org Chem, 1976, 41, 8) (6.05 g, 19.2 mmol) was dissolved in dry THF (500 ml) and cooled to −78° C. After 15 min the reaction mixture was treated with 3-(tert-butyldimethylsilyloxy)-1-iodopropane (6.3 g, 1.1 equiv.) (for a synthesis, see J. Chem. Soc. Perkin Trans. 1, 1190, 1111). After a further 15 min. the cooling bath was removed and the reaction allowed warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, and partitioned between ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in hexane. Product-containing fractions were combined and evaporated to a colourless oil) 5.61 g. This was dissolved in THF (100 ml) and treated with tetra-n-butyl ammonium fluoride (2M solution in THF, 16 ml) and stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel eluting with 1-100% ethyl acetate in hexane, to afford the title compound (2.48 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCI
Reactant: O=C(O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1occc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromofuran-2-carboxylic acid (23.5 g), iodoethane (11.8 mL) and potassium carbonate (25.6 g) in DMF (200 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with diethylether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in hexane, passed through a silica gel (NH) layer, and the eluate was concentrated under reduced pressure to give the title compound (23.0 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH3:10].Br[CH2:24][CH:25]([CH3:27])[CH3:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:22])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:10]
Reactant: CC(C)CBr
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (4.88 mL of 0.29 M stock solution, 1.41 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid ethyl ester (300 mg, 1.28 mmol) in tetrahydrofuran/hexamethylphosphoramide (3.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 1-bromo-2-methyl-propane (1.53 mL, 1.41 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 6 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (1 mL). This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid ethyl ester (356.4 mg, 95.8%) as a clear oil: EI-HRMS m/e calcd for C14H18Cl2O2 (M+) 288.0683, found 288.0677.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C>[Br:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (0.66 g, 2.62 mmol) and N-bromosuccinimide (0.93 g, 5.2 mmol) in acetic acid (12 mL) was heated to reflux for 24 hours. An additional portion of N-bromosuccinimide (0.5 g, 2.8 mmol) was added and the reaction refluxed another 16 h. The reaction mixture was allowed to cool to room temperature, poured over ice and the resulting white solid was collected and purified by silica gel chromatography, eluting with dichloromethane to obtain ethyl 4-bromo-5-(4-chlorophenyl)isoxazole-3-carboxylate (0.62 g, 1.88 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]#[N:13])[C:5]2=O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1c[nH]c2ccc(I)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2ccc(I)cc2c1Cl
Yield: 98 %

Procedure:
A mixture of 6 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (example 14b) (100 g, 0.34 mol) in phosphorus oxychloride (300 mL) was refluxed under N2 for 7 h. After cooling, the solvent was removed by rotary evaporator and then by the oil pump. Sat. sodium bicarbonate (200 mL) and ice water were slowly added. The solid was collected by filtration, washed with sat. sodium bicarbonate, water and dried to obtain 4-chloro-6-iodo-quinoline-3-carbonitrile (58 g, 98%) as a yellow solid. LC-MS m/e 315 (MH+).