Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(#N)[CH:11]([CH2:13][C:14]#[N:15])O.[NH:17]1CCCCC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:13]([C:11]#[N:17])[C:14]#[N:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C1CCNCC1
Reactant: N#CCC(O)C#N
Solvent: C1COCCO1
Product: N#CC(C#N)=Cc1cccc(Br)c1

Procedure:
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malonitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[N:10]=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=1>>[Cl:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[N:10]=[C:9]([C:29]([F:32])([F:30])[F:31])[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 0 °C
Yield: 65.59 %

Procedure:
To a solution of chlorosulphonic acid (605 mmol, 40.4 ml) was added 4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.0 g, 12.1 mmol, prepared according to the procedure described in PCT/IB03/02879) slowly under continuous stirring at 0° C. until the completion of the addition. The reaction mixture was further stirred at 32° C. until TLC confirmed the completion. Subsequently the resulting reaction mass was poured slowly under vigorous stirring onto crushed ice and the solid obtained was filtered, washed thoroughly with water (100 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (2.75 g, yield 65.59%, purity by HPLC 98.17%); m.p: 207-210° C. 1H-NMR (400 MHz, CDCl3) δ: 3.01 (s, 3H), 7.511-7.515 (d, 2H), 7.53-7.67 (m, 1H), 7.72-7.76 (t, 1H), 7.86-7.89 (m, 3H), 8.11-8.13 (d, 1H). IR (KBr) cm−1: 1557, 1524. MS m/z: 511.6(M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10](N)([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.C=O.[C:33](O)(=O)C.[C:37]([BH3-])#[N:38].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([N:38]([CH3:37])[CH3:33])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccnc2ccccc12)C(F)(F)F
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(Cc1ccnc2ccccc12)(N(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
A solution of 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine (42.0 mg, 0.1 mmol) and the formaldehyde (1.49 ml, 20 mmol) in acetonitrile (2 ml) was stirred for 30 minutes at room temperature. The reaction mixture was acidified with acetic acid (57 μL, 1.0 mmol) and treated with sodium cyanoborohydride (31.4 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 15 h and quenched with NaHCO3 (sat. 2 ml). Phases were separated and the aqueous layer was extracted with CHCl3 (3×2ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was dissolved in Et2O and treated with HCl (2M in Ether) until the mixture was acidic (pH˜2). The ether layer was decanted and the salt was washed with ether (5×2 ml) and dried. The solid was dissolved in CHCl3, extracted with NaHCO3 (sat.), phases were separated and the aqueous layer was extracted with CHCl3 (2×4 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified on SiO2 (20%–30%, EtOAc: Hexanes) to give 12.5 mg (28%) of the title compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:24])[C:20]#[C:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:19](=[O:24])[CH:20]=[C:21]([CH2:22][CH3:23])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCC#CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine and ethyl 2-pentynoate according to the procedures employed for the preparation of the compound in Example 95. [α]D25 −29.20 (c 0.5, CHCl3)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:9])[CH3:8]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:9][CH2:7][CH3:8]
Reactant: C=CC(=O)OC
Reactant: CCN
Solvent: CO
Product: CCNCCC(=O)OC
Temperature: -20 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure to afford the title compound as a colorless liquid (2.41 g, 30% yield). 1H NMR (CDCl3) 1.11 (t, 3H, J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t, 2H, J=6.58 Hz), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][F:5])=[O:3].C(O)[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O.[O:18]([F:20])[F:19].[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([Sn](C)(C)C)=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22]>C(Cl)(Cl)(Cl)F.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([F:5])=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22].[CH3:1][C:2]([O:4][F:5])=[O:3].[O:18]([F:20])[F:19]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1[Sn](C)(C)C)NC=O
Agent: CC(=O)OF
Agent: FOF
Agent: OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O
Solvent: FC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1F)NC=O

Procedure:
The electrophilic fluorinating agent, CH3COOF (prepared from 200 μmol) of F2 in 1% He, (Bida, G. T., Satyamurthy, N. and Barrio, J. R. (1984) The synthesis of 2-[18F]fluoro-2-deoxy-D-glucose using glycals: A reexamination. J. Nucl. Med. 25, 1327) F2 (1% in He, 200 μmol) or OF2 (1% in He, 200 μmol), was bubbled into a solution of trimethyltin derivative 6 (0.123 g, 200 μmol) in Freon-11 (CFCl3) (20 mL) at room temperature over a period of 30 min. The reaction mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 1M Na2S2O5 (2×20 mL), water (2×20 mL) and dried (MgSO4). Evaporation of solvents gave a yellow syrup which was chromatographed (silica gel, diethyl ether) to yield a colorless viscous oil 9 (41 mg, 43% in the case of CH3COOF), (65 mg, 69% for F2), (62 mg, 66% for OF2).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: OB(O)c1cccnc1
Reactant: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(-c3cccnc3)c2nc1OC
Yield: 29.2 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (Preparation 108, 0.2 g, 0.519 mmol), 3-pyridylboronic acid (Rec. Trav. Chim. Pays-Bas. 84, 439 (1965)) (0.077 g, 0.623 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) and potassium carbonate (0.143 g, 1.038 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was heated under reflux for 16 hours. After being cooled, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 99:1, by volume) to afford the title compound (0.051 g, 29%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The above obtained crude 2,4-dibenzyloxybenzyl chloride [VII] was dissolved in dimethyl sulfoxide (150 ml) and then thereto was added sodium cyanide (4 g), followed by stirring for 2 hours at room temperature (20° C.). The reaction mixture was added to water (1 liter) and extracted with dichloromethane (1 liter). The dichloromethane extract was concentrated under reduced pressure and the residue was purified by a silica gel column [inner diameter: 10 cm, length 50 cm; developer: dichloromethane-hexane 1:1 (v/v) mixed solution] and furthermore, was recrystallized from diethyl ether-hexane 2:1 (v/v) mixed solution to obtain 2,4-dibenzyloxyphenylacetonitrile [VIII] (14.3 g, yield from [VI]: 70%). Melting point: 99°-100° C.
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:12]([Cl:14])=[N:11][C:10]([NH2:15])=[N:9][C:8]=2[N:7]([CH2:16][C:17]2[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=2)[CH:6]=1)#CC=C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:48]C)C=C4)N(CC2)C1.C[C:86]([OH:89])([CH3:88])[CH3:87].C1COCC1.O>>[NH2:15][C:10]1[N:11]=[C:12]([Cl:14])[C:13]2[C:5]([C:1]#[C:87][C@@H:86]([OH:89])[CH2:88][OH:48])=[CH:6][N:7]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:8]=2[N:9]=1
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2cc(C#C[C@@H](O)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
Treatment of 5-(but-3-en-1-ynyl)-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (see example 46) (35 mg) with AD-mix-β (Aldrich, 540 mg) in t-BuOH:THF:water 1:1:1 (6 mL) at rt overnight, followed by work-up and reverse-phase preparative HPLC gave the title compound (10 mg), as a solid. HPLC Rt=4.13 min
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#N)=[N:12][CH:13]=1.Cl.[OH2:19]>CCO>[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:19])=[O:1])=[N:12][CH:13]=1
Reactant: O
Reactant: N#Cc1ccc(COCC(F)(F)F)cn1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(COCC(F)(F)F)cn1
Yield: 91 %

Procedure:
Powdered potassium hydroxide (0.331 g, 5.90 mmol) was dissolved in EtOH (2 mL) and added to 5-[(2,2,2-trifluoroethoxy)methyl]pyridine-2-carbonitrile (Intermediate 226, 0.255 g, 1.18 mmol). The mixture was heated to 110 C for 16 h. After cooling the residue was dissolved in water (3 mL), acidified to pH 1 by adding 10% aq. hydrochloric acid and extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated to afford the title compound as a brown gum (0.252 g, 91%), which was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=236 Found: m/z=236, Rt=0.83 min (82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:14][C:13](=S)[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:17].C(OO)(C)(C)C>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[CH2:10][O:11][CH2:12][C:13]([NH2:17])=[N:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(c2ccc(F)c(Br)c2)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: CO
Solvent: O
Product: CC1(c2ccc(F)c(Br)c2)COCC(N)=N1
Reaction time: 8 h

Procedure:
A solution of (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-morpholin-3-thione (intermediate XVIII-1) (202 mg, 0.7 mmol) in methanol (15 ml) was treated with a solution of ammonia in methanol (7M, 5.7 ml, 39.8 mmol) and an aqueous solution of tert-butyl hydroperoxide (70% in water, 0.91 ml, 6.6 mmol). After stiffing at room temperature overnight, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with water, then dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a colorless gum (109 mg, 57% of theory). MS (ISP): m/z=287.2 [M+H]+, 289.1 [M+2+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:24][C:19]1[CH:20]=[C:21]2[C:16](=[N:17][CH:18]=1)[N:15]=[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:23]=[CH:22]2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3cc(Br)cnc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc2nc(C3CCNCC3)ccc2c1

Procedure:
A solution of bromide 3-4 (3.5 g, 8.92 mmol), CH2Cl2 (20 ml) and TFA (10 ml) was stirred for 1.0 h. The reaction was concentrated and then azeotroped with toluene. The residue was dissolved in 1N NaOH and then extracted with CHCl3. The CHCl3 portion was washed with brine, dried (MgSO4) and concentrated providing amine 3-5 as a brown solid.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22]O)[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22][I:1])[C:18](=[O:24])[C:17]3[C:12](=[C:13]([O:25][CH3:26])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: II
Reactant: COc1cccc2c(=O)n(CCCO)c(COc3ccc(Cl)cc3)nc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c(=O)n(CCCI)c(COc3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
Iodine (1016 mg, 4 mmol) was added to a mixture of the product from Step A above, triphenylphosphine (1050 mg, 4 mmol) and imidazole (545 mg, 8 mmol) in toluene (20 mL) at 0° C. The reaction mixture was slowly allowed to warm to room temperature and was stirred for 17 h and diluted with CHCl3. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was chromatographed on SiO2-gel using 30% EtOAc/hexanes to yield the product as a yellow oil (450 mg, 35%). API-MS: 485 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.35 (t, 1 H), 7.2 (d, 2 H), 7.1 (d, 1 H), 6.9 (d, 2 H), 5.15 (s, 2 H), 4.1 (t, 2 H), 3.93 (s, 3 H), 3.9 (s, 3 H), 3.15 (t, 2 H), 2.23 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1.[CH2:17]([Li])CCC.CI>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:17])[CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCc1cccc2c1NCCC21OCCO1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CN1CCC2(OCCO2)c2cccc(CO)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxymethyl-4,4-ethylenedioxy1,2,3,4-tetrahydroquinoline (2.5 g) in tetrahydrofuran (30 ml) was added n-butyllithium (14.5 to 17% solution in n-hexane) (10 ml) at --40° C. and stirred for 30 minutes. Then methyl iodide (1.9 g) was added to the reaction mixture and the mixture was stirred for 3 hours at -30° C. to -10° C. and for 30 minutes at -5° C. After distilling off the solvent, n-hexane-ethyl acetate was added to the resulting residue and the insoluble matter was filtered off. The filtrate was concentrated to give 8-hydroxymethyl-4,4-ethylenedioxy-1-methyl-1,2,3,4-tetrahydroquinoline (1.9 g).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][C:12]2[S:13][C:14]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[CH:15][C:16]=2[CH2:17][CH2:18]O)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.C(#N)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][C:12]2[S:13][C:14]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[CH:15][C:16]=2[CH2:17][CH2:18][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: CSc1ncc(Cl)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Cl)c(-c2cc(CCN3CCOCC3)c(Cc3ccc(F)cc3)s2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Methanesulfonyl chloride (59 mg, 0.52 mmol) was added to a mixture of 2-(2-(4-fluoro-benzyl)-5-(5-chloro-2-(methylthio)pyrimidin-4-yl)thiophen-3-yl)ethanol (170 mg, 0.43 mmol) and diisopropylethylamine (72 mg, 0.55 mmol) in dichloromethane (8 mL) at 0° C. After stirring at 0° C. for 1 h, the solvent was removed in vacuo. Acetonitrile (5 mL) and morpholine (112 mg, 1.29 mmol) were added to the residue and the mixture was heated to 70° C. overnight. After cooling to rt solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with methanol (1 M ammonia)/dichloromethane (1:20) to afford the title compound (148 mg, 74%). MS (M+H)+ 464/466.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C=O)C>[CH3:31][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCBr
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one (0.39 g, 0.79 mmol) in DMF (10 mL) was added pyrrolidine (0.45 g, 6.37 mmol). The reaction mixture was stirred at room temperature for 4 hours. Then, water was added and product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.32 g (83%). MP 65-68° C. 1H NMR (400 MHz, CDCl3): δ 9.05 (br s, 1H), 7.63 (s, 2H), 6.78 (s, 1H), 6.42 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 2.94 (m, 2H), 2.64 (br s, 4H), 2.38 (s, 6H), 1.84 (m, 4H), 1.46 (m, 3H), 1.42 (m, 3H). MS (ES) m/z: 480.29 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(F)cc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
3-Amino-6-fluoro-2-methoxyquinoxaline (580 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 740 mg of the titled compound (yield, 93%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](C)[C:12]([O:14][C:15]([CH3:18])(C)C)=[O:13])=[CH:7][CH:6]=1)(O)=O.[C:20](=[O:23])([O-])[O-:21].[K+].[K+].C(Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29]C=1>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:1][C:20]([O:21][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:23])=[CH:10][CH:9]=1)[C:18]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Reaction time: 24 h
Yield: 184 %

Procedure:
To a stirred suspension of 1,1-dimethylethyl 4-(carboxymethyl)phenylpropanoate (5.3 g, 20.0 mmol) and potassium carbonate (2.8 g, 20.0 mmol) in DMF (30 mL) was added benzyl bromide (3.42 g, 20 mmol). After stirring for 24 h, the solvent was removed in vacuo and the residue was extracted with hexanes (100 mL). Filtration and removal of the solvent under reduced pressure gave 1,1-dimethylethyl 3-[4-(2-benzyloxy-2-oxo-ethyl)phenyl]propanoate (6.5 g, 18.4 mmol) as a colorless liquid in 92% yield.