Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:6].S(Cl)(Cl)=O>CN(C=O)C>[C:5]1(=[O:6])[C:7]2=[N:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]2[CH2:2][CH2:3][NH:4]1
Reactant: O=C(NCCO)c1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1NCCn2c1nc1ccccc12
Temperature: 0 °C
Yield: 52.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 152a (1.41 g, 6.84 mmol) and DMF (10 mL), and the reaction mixture was cooled to 0° C. A solution of thionyl chloride (896 mg, 7.53 mmol) in DMF (5 mL) was added dropwise. The reaction was heated at 150° C. for 2 h. After this time, the solvent was removed under reduced pressure. The resulting residue was partitioned between water (20 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 52% yield (672 mg) of 152b as a brown solid: mp>250° C.; 1H NMR (500 MHz, DMSO-d6) d 8.53 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.66 (d, 1H, J=9.0 Hz), 7.40 (t, 1H, J=9.0 Hz), 7.31 (t, 1H, J=9.0 Hz), 4.41 (t, 2H, J=6.0 Hz), 3.71 (m, 2H); MS (APCI+) m/z 188.4 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2C(=O)C(C)(C)C)=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[CH3:25][NH:26][CH3:27].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[CH3:25][N:26]([CH2:2][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)[CH3:27]
Reactant: CC(C)(C)C(=O)n1ccc2ccc(C(=O)CCl)cc21
Reactant: CNC
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCc1ccc2cc[nH]c2c1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a stirred solution of 6-Chloroacetyl-1-pivaloylindole (300 mg, 1.08 mmol) in THF (5 ml) were added successively, at room temperature, NaHCO3 (453.6 mg, 5.4 mmol) and a solution of 2M N,N-Dimethylamine in THF (2.7 ml, 5.4 mmol). The reaction mixture was then refluxed for four hours. After cooling to room temperature, the mixture was diluted with water (15 ml) and the organic layer extracted twice with dichloromethane (2×50 ml). After washing sequentially with water and brine, the organic layer was dried over sodium sulfate, and the solvent removed in vacuo. LiAlH4 (10.8 ml, 1M in THF, 10.8 mmol) was added to a solution of the crude product in THF (5 ml) and the reaction mixture heated at reflux overnight. After cooling to room temperature, the reaction mixture was quenched with Rochelle's salt (1 M, 3 mL) and silica gel and passed through a frit using methanolic ammonia in dichloromethane (0-10%). The 5% fraction was further purified by flash chromatography (silica gel, 3% methanolic ammonia in dichloromethane) yielding the product (176 mg, 87%) of the title product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH2:19][CH2:18]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:21](=[O:22])[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH:17]1[CH2:19][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccc(F)c(Oc2ccccc2)c1)C(c1ccc(Cl)cc1)C1CC1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
9.4 g (0.043 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 9.9 g (0.043 mol) of α-cyclopropyl-4-chlorophenyl-acetic acid chloride were dissolved in 100 ml of anhydrous toluene, and 4 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 14.9 g (84.4% of theory) of α-cyclopropyl-4-chlorophenyl-acetic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a yellow oil. The structure was confirmed by the H-NMR spectrum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:10]([OH:39])[CH2:11][N:12](C(OCC1C=CC=CC=1)=O)[C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:47]>CO.[Pd]>[ClH:47].[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:10]([OH:39])[CH2:11][NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)N(CC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H](NCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(3S)-1-[N-[3-[[(t-Butyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, t-butyl ester (550 mg, 0.86 mmol) was dissolved in methanol (35 ml) and hydrochloric acid (1N, 0.86 ml). Palladium on carbon catalyst (10%, 200 mg) was added and the solution was stirred under an atmosphere of hydrogen overnight, filtered through Hyflo and evaporated yielding 450 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][NH2:24])[CH:17]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:24][CH2:23][CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccnc1
Product: Clc1nccc(-c2cccc(CNCCc3cccnc3)c2)n1

Procedure:
Intermediate 1 was coupled with 2-pyridin-3-yl-ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 325.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:8]=[C:9]([CH3:23])[CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[N:12]=3)[CH:6]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.71) (0.43 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.19 g) which was subsequently deprotected.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>COC(C)(C)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH:23]([CH3:25])[CH3:24])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC(C)N
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC#CCOc1cc(NC(C)C)ncn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To 4 ml of dimethylsulfoxide were added 365 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 332 mg of potassium carbonate, and 591 mg of isopropylamine, followed by stirring at 70° C. for 6 hours. The reaction mixture was then left for cooling to room temperature, diluted with tert-butyl methyl ether, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 339 mg of 4-(2-butynyloxy)-6-(isopropylamino)pyrimidine (the present compound (106)).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:10][CH:11]1[CH:15]([CH:16]=O)[CH2:14][CH:13](OC)O1>C(O)(=O)C>[CH:1]1([N:8]2[CH:13]=[CH:14][C:15]([CH:11]=[O:10])=[CH:16]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: NC1CCCCCC1
Solvent: CC(=O)O
Product: O=Cc1ccn(C2CCCCCC2)c1

Procedure:
A mixture of 38.0 g of cycloheptylamine and 50 ml of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde in 300 ml of glacial acetic acid is stirred under reflux for 3 hours. The solution is evaporated to dryness at 60° under reduced pressure. The residue is then dissolved in a 1:1 mixture of ether and hexane, the solution is treated with charcoal and evaporated to dryness to give 1-cycloheptyl-1H-pyrrole-3-carboxaldehyde as an oil. The aldehyde (30 g) is then added dropwise to a mixture of 35 ml of triethyl phosphonoacetate in 1 liter of toluene to which had been added 9.5 g of sodium hydride. The reaction mixture is stirred in an ice bath for 2 hours and then at room temperature overnight, washed first with ice cold dilute hydrochloric acid, then with brine, dried over magnesium sulfate, treated with charcoal and evaporated to dryness to yield ethyl (E)-3-(1-cycloheptyl-1H-pyrrol-3-yl)-2-propenoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]2[CH2:20][C:21]([OH:23])=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:5]2([CH:20]=[C:21]=[O:23])[N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: Cc1cc2c(cc1C)C(CC(=O)O)N(c1cccc(F)c1)C2=O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(C=C=O)(N1CCN(C)CC1)N(c1cccc(F)c1)C2=O
Yield: 89 %

Procedure:
5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyl-isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (0.50 g, 1.6 mmol), 1-methylpiperazine (0.16 g, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole hydrate (0.25 g, 1.6 mmol) were stirred in tetrahydrofuran (40 ml) at 25° C. for 16 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 0.56 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5](CC)(CC)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[OH:24])=[C:11]([F:25])[CH:10]=1)C.C1COCC1.C([O-])(O)=O.[Na+].[OH-].[Li+].Cl>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:10][C:11]=2[F:25])=[C:17]([OH:24])[CH:18]=1)[CH3:23]
Reactant: CCOC(=O)C(CC)(CC)CCOc1ccc(Oc2ccc(CC)cc2O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(OCCCC(=O)O)cc2F)c(O)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of ethyl ethyl 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid ethyl ester (0.16 mmol; 58 mg), in a THF/water mixture (1/1; 1 mL) was added lithium hydroxide (0.64 mmol; 15 mg). The reaction was heated 1 hour at 60° C. After cooling to 0° C., the reaction was treated with concentrated HCl, and extracted with ethyl acetate (3*2 mL). Combinated organic phases were dried over Na2SO4 and concentrated in vacuo. The title compound (0.16 mmol; 54 mg; quantitative) was obtained as a clear oil, used without purification.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br.[NH2:17][C@@:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].N1C=CN=C1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:26][C@:18]1([N:17]2[C:4](=[O:15])[C:5]3[C:6](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[N:7]=[C:2]2[CH3:1])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25]
Reactant: C[C@]1(N)CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: Br
Agent: c1c[nH]cn1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@@]1(C)CCC(=O)NC1=O
Temperature: 45 °C
Reaction time: 40 h
Yield: 21.8 %

Procedure:
A mixture of 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one (2.0 g, 9.7 mmol), (S)-3-amino-3-methylpiperidine-2,6-dione hydrobromide (2.2 g, 9.7 mmol), imidazole (1.5 g, 21 mmol), and triphenylphosphite (3.7 g, 12 mmol) in DMF (20 mL) was stirred under nitrogen at 45° C. for 40 hours. The mixture was evaporated, and the residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient. The product eluted at 15% acetonitrile, providing (S)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione as a yellow solid (0.70 g, 22% yield); 1H NMR (DMSO-d6) δ 1.94 (s, 3H, CH3), 2.35-2.40 (m, 1H, CHH), 2.45-2.59 (m, 2H, 2CHH), 2.71-2.83 (m, 4H, CH3, CHH), 7.75-7.82 (m, 2H, Ar), 7.95 (dd, J=8, 8 Hz, 1H, Ar), 10.86 (s, 1H, NH).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:18]([Ge:20](Cl)([Cl:23])[CH2:21][CH3:22])[CH3:19]>O1CCCC1.CCCCCC>[Cl:23][Ge:20]([CH2:21][CH3:22])([CH2:18][CH3:19])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: CC[Ge](Cl)(Cl)CC
Reactant: c1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Ge](Cl)(CC)C1(c2ccccc2)SCCCS1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
19.63 g (0.10 mol) 2-phenyl-1,3-dithian was dissolved under argon in 200 ml anhydrous tetrahydrofuran (THF) in a dry 500-ml three-necked flask with 50 ml dropping funnel, internal thermometer, magnetic stirrer and septum. The solution was cooled to −10° C. 44 ml of a 2.5 molar solution of n-butyllithium (0.11 mol) in n-hexane was added dropwise at −5° C. over a period of 50 min. After the addition was complete, the green solution was stirred for 2 h at 0° C. It was then added dropwise within 45 min to a solution, cooled to −72° C., of 20.16 g (0.10 mol) diethylgermanium dichloride in 500 ml anhydrous THF, wherein the temperature did not exceed −65° C. The reaction mixture was stirred for a further 16 h in a thawing cold bath, then concentrated on the rotary evaporator. 100 ml dry n-hexane was added to the residue followed by stirring for 1 h at room temperature. The suspension was filtered and the filtrate was concentrated on the rotary evaporator and dried under fine vacuum. The oily, yellow crude product was purified by means of high-vacuum distillation (b.p.: 135-150° C./4×10−5 mbar). 27.23 g (75% of the theoretical value) chlorodiethyl(2-phenyl-1,3-dithian-2-yl)germanium was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(F)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 5-fluoro-2-hydroxybenzaldehyde (5.0 g, 35.69 mmol, 1.00 eq.) and potassium carbonate (7.97 g, 57.10 mmol, 1.60 eq.) in DMF (60 mL), benzyl bromide (4.54 mL, 37.47 mmol, 1.05 eq.) was added dropwise. The reaction mixture was refluxed for 2 hours, then allowed to cool to r.t. and poured into 100 mL of cold water and extracted with AcOEt. The organic extract was washed with 10% aq. NaOH soln. and sat. aq. NaCl soln., dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to Heptane+30% AcOEt) to yield 2-benzyloxy-5-fluoro-benzaldehyde as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]1[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:33])[N:17]=[CH:16]2>CO.C(OCC)(=O)C.[Pd]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:33])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(Nc4c(C)cccc4N)ncc3c2)c1Cl
Reaction time: 8 h

Procedure:
6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine (5.5 g, 11.33 mmol) was taken up in methanol (200 ml) and Ethyl Acetate (100 ml), 10% Pd/C (650 mg) was added. The mixture was stirred under H2 balloon overnight. The reaction mixture was filtered through celite and the solvent was removed to give N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)-6-methylbenzene-1,2-diamine in quantitative yield. It was carried on to the next step without further purification. MS (ES+) C23H20Cl2N4O2, 455 [M+H]+
Reaction SMILES: [OH:1][CH2:2][N:3]([CH3:24])[N:4]=[N:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][N:3]([CH3:24])[N:4]=[N:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)(=[O:27])[CH3:26]
Reactant: CN(CO)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCN(C)N=Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(3′-chlorophenyl-amino)-6-aminoquinazoline (100 mg, 0.318 mmol) in acetonitrile (20 mL) kept at 0° C. in an ice bath, nitrosonium tetrafluoroborate (74.3 mg, 0.637 mmol) was added dropwise. The solution was stirred for 20 min and 0.9 mL of a mixture of methylamine 40% (0.075 mL, 0.954 mmol), formaldehyde 37% (0.75 mL, 9.54 mmol), and concentrated HCl (0.1 mL) was added all at once. The diazonium solution was subsequently alkalinized with potassium carbonate (400 mg, 2.86 mmol) and the precipitate was filtered to give a white solid contaminated with excess potassium carbonate. The precipitate was therefore re-suspended in THF and the resulting solution filtered. The organic solvent was further evaporated to give 6-(3-hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown solid (90 mg, 73%). 6-(3-Hydroxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.258 mmol) was dissolved in pyridine (2 mL) after which acetic anhydride (0.055 mL, 0.516 mmol) was slowly added. The solution was further kept on ice for 1.5 h and the pyridine evaporated as an azeotrope with toluene to give 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline as a pure brown residue (105 mg, 95%). 6-(3-Acetoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline (100 mg, 0.260 mmol) was dissolved in anhydrous methanol (2.5 mL) and stirred at room temperature for 24 h. The methanol was then evaporated to provide the title compound 6-(3-methoxymethyl-3-methyl-triazenyl)-4-(3′-chlorophenyl-amino)quinazoline) as a pure brown residue (91 mg, 98%): EI m/z 357.0 (MH+), 253.2 (M-3-methoxymethyl-3-methyl-triazene); 1H NMR (400 MHz, DMSO-d6) d 9.94 (s, 1H, NH), 8.60 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H, J=9.2 Hz), 7.88 (d, 1H, J=6.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.39 (t, 1H, J=6.6 Hz), 7.14 (d, 1H, J=9.2 Hz), 5.17 (s, 2H, CH2), 3.25 (s, 3H, CH3,), 3.24 (s, 3H, CH3).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH3:3].[CH2:18](O)[CH2:19]CC>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])[CH2:3][CH2:18][CH3:19]
Reactant: CCCCO
Reactant: CCOC(=O)C=C(CC)C(C)CC=C(C)C
Agent: [Na]
Solvent: CC(=O)O
Product: CCCCOC(=O)C=C(CC)C(C)CC=C(C)C
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 100 mg of sodium in 85 ml of n-butanol is placed in a flask filled with nitrogen and cooled to ca 5° C. At this temperature, 20 g (0.09 mol) of 3-ethyl-4,7-dimethyl-2,6-octadienoic acid ethyl ester are added. The mixture is then warmed to 60° C for 5 hours and to 100° C for 3 hours. For the working-up, the mixture is acidified with a few drops of glacial acetic acid and then the major part of the n-butanol is distilled off on a rotary evaporator. The residue is taken up in n-hexane, washed twice with sodium bicarbonate solution and three times with water, dried over sodium sulphate and evaporated. The crude product (19.3 g) is fractionally distilled. There are obtained 16.4 g (73%) of pure 3-ethyl-4,7-dimethyl-2,6-octadienoic acid n-butyl ester of boiling point 90°-92° C/0.04 mm Hg; nD20 = 1.4677.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][SH:15])[CH2:11][O:12][C:8]=2[CH:7]=1.CCN(C(C)C)C(C)C.CN(C=O)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][S:15][CH2:14][CH2:13][C@H:10]1[C:9]2[CH:16]=[CH:17][C:6]([O:5][CH2:4][C:3]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=3[Cl:1])=[CH:7][C:8]=2[O:12][CH2:11]1)[CH3:43]
Reactant: SCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a mixture of 2-((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)ethanethiol (30 mg), DIPEA (0.029 mL) and DMF (dry) (15 mL) was added ethyl 2-bromoacetate (21.15 mg). The mixture was stirred at room temperature under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (25.0 mg).