Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:5][C:4]=1B(O)O)[CH3:2].FC(F)(F)S(O[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:25][C:24]=1[CH2:33][CH3:34])(=O)=O>>[CH2:12]([O:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:25][C:24]=2[CH2:33][CH3:34])[CH:5]=1)[CH3:13]
Reactant: CCC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(CC)c1
Reactant: CCOCOc1ccc(CC)c(B(O)O)c1
Product: CCOCOc1ccc(CC)c(-c2ccc(C(=O)CC)cc2CC)c1

Procedure:
In a manner similar to that of Example 1(g), by reacting 2 g (8.9 mmol) of 2-ethyl-5-ethoxymethoxyphenylboronic acid with 2.1 g (6.9 mmol) of 2-ethyl-4-propionylphenyl 1,1,1-trifluoromethanesulfonate, a black oil is obtained, which is used without further purification for the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:36]OC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:25])=[O:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 515.29 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride, yielding 2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:34][CH:33]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-tert-butoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.39 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[C:17]1[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and o-anisoyl chloride in a similar manner as described above to give a pale orange solid (67% yield). 1H-NMR (CDCl3): δ 9.06 (s, 1H), 8.31 (d, 1H), 8.25 (dd, 1H), 7.60 (d, 1H), 7.46 (m, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H), 7.10 (m, 1H), 6.96 (d, 1H), 5.31 (m, 1H), 3.91 (s, 3H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 399 (M−1).
Reaction SMILES: NC1C=CC=CN=1.[I-].[NH2:9][N+:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]2[N:16]=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:28][CH:29]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1cccc[n+]1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Nc1ccccn1
Agent: [I-]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nc3ccccn3n2)cc1
Temperature: 85 °C
Yield: 74 %

Procedure:
2-Aminopyridine was converted to 1,2-diaminopyridinium iodide from a known literature method (J. Org. Chem., 31:260-265 (1996)). 1,2-Diaminopyridinium iodide (0.270 g, 1.1 mmol) was treated with 4-tert-butyl-benzoyl chloride (0.432 g, 2.2 mmol) in pyridine (2 mL). The reaction was heated at 85° C. in a sealed tube for 3 h, at which time the mixture was cooled to room temperature. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate extract was dried over magnesium sulfate and concentrated. The crude material was purified by flash silica gel chromatography, eluting with 25% ethyl acetate/hexanes (Rf=0.4) to yield 0.205 g (74%) of the purified product. MS (ES) m/z 252.2; HPLC (Method B): r.t.=6.7 min., purity 100% at 210-370 nm, 100% at 254 nm. HRMS: calcd for C16H17N3+H+, 252.14952; found (ESI, [M+H]30 ), 252.149.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:13])=[CH:10][N:11]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].CCN(CC)CC>CO>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12](=[O:13])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][N:11]=1)=[O:31]
Reactant: COc1ccccc1N=C=O
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccccc1NC(=O)NCCCNc1ncc(C(=O)c2ccccc2C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
A mixture of 12.5 mg (0.04 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone hydrochloride, 7.6 mg (0.05 mmol) 2-Methoxyphenyl isocyanate and 39 ul NEt3 in 1 ml methanol was stirred for 16 h at room temperature. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 7.9 mg (47%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:64]([NH2:69])[CH2:65][CH:66]([CH3:68])[CH3:67]>CN(C=O)C>[CH2:64]([NH:69][C:19](=[O:21])[CH2:18][N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:22])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 900 mg of 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetic acid (˜2.32 mmol), 744 mg of TBTU (2.32 mmol), 313 mg of HOBt (2.32 mmol) is dissolved in 25 mL of DMF. By addition of 985 μL of DIPEA (5.79 mmol, 2.5 eq) a pH value is adjusted to ˜9. 539 μL of isopentylamine (4.63 mmol) is added and the mixture is stirred at RT for 2.5 h. The solvent is removed in vacuo and the obtained residue is taken up in 100 mL of DCM and subsequently washed with 10% citric acid (3×75 ml), saturated NaHCO3 solution (3×75 ml) and brine (75 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo in dryness. Brown solid is obtained and it is suitable for further processing without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34]CC=C)=[CH:30][CH:29]=2)[C@H:10]([O:38][CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Li+].CC(C)=O>O1CCCC1.C(=O)([O-])O.[Na+].CC(O)=O.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[C@H:10]([O:38][CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(O)cc2)cc2ccccc12
Temperature: 5 °C
Reaction time: 4 h

Procedure:
0.40 g (0.63 mmol) of (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl -[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester, 1.4 mg (0.0063 mmol) of palladium-II-acetate and 3.3 mg (0.0126 mmol) of triphenylphosphin were dissolved in 2 ml of tetrahydrofuran. After cooling to 5° C., 21.7 mg (0.947 mmol) of lithiumborohydride were added and the reaction mixture stirred for 4 hours without cooling. Thereafter, the reaction mixture was again cooled to 5° C. and treated with 0.32 ml of acetone, then diluted with 5 ml of saturated sodium hydrogen carbonate solution and extracted twice with 5 ml of ether. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was separated on silica gel using a mixture of dichloromethane/ethyl acetate (4/1) as the eluent and yielded 0.343 g (0.578 mmol), 91.5%, (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 594 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:34]=[C:35]([CH2:37][O:3][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]4[CH:17]=[CH:16][N:15]=[CH:14]4)=[CH:6][CH:5]=3)[N:36]=2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)cc1
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
Sodium hydride (440 mg) was added, at room temperature, to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (2.02 g) in N,N-dimethylformamide (50 ml). The mixture was stirred for 1.5 hour, to which was added 2-(4-benzyloxyphenyl)-4-chloromethyloxazole (3.60 g). The mixture was stirred for further 3 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with ethyl acetate-methanol (50:1, v.v) was recrystallized from ethanol to give 2-(4-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (2.88 g, 62%) as colorless prisms, mp 133-134° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1)[CH3:2].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: CCc1ccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-(4-ethylphenyl)-9H-fluoren-9-ol (Example 3o) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: CS(O)(=O)=O.C(N[C:9](=[O:13])[NH:10][CH2:11][CH3:12])C.C(N[C:17](=[O:21])[NH:18][CH2:19][CH3:20])C.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>CC1C=CC=CC=1C>[CH3:27][C:22]1[C:19](=[CH:20][C:11](=[CH:12][CH:23]=1)[N:10]=[C:9]=[O:13])[N:18]=[C:17]=[O:21]
Reactant: CCNC(=O)NCC
Reactant: Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A mixture of 12.7 g 2,4-toluene bis (diethylurea) in 248 g o-xylene was charged to a 500 ml fluted flask equipped with a bottom take-off, a mechanical stirrer using a 1.5 inch "Teflon" crescent-shaped paddle, a condenser, and a thermocouple to monitor reaction temperature. The mixture was heated to 120° C. and then 8.75 g methane sulfonic acid was added in one portion. The mixture was stirred for 15 min at 120° C. and then the phases were allowed to settle at 50° C. The bottom salt phase was drawn off through the bottom take-off. Analysis of the xylene phase by HPLC and infrared analysis showed 100% conversion of the toluene bis (diethylurea) with a 98% yield of toluene diisocyanate. The xylene phase was then transferred to a round bottom flask equipped with a 12" Vigreux column and a distillation head for vacuum distillation. Octadecane, 65 g, was added to the flask and then the xylene was distilled overhead at 40 mm Hg. TDI was then distilled over 10 mm Hg. A heart cut of TDI containing 6.1 g TDI was obtained for an isolated yield of 88% for toluene diisocyanate.
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([O:11]C)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(Cl)(Cl)Cl>[F:1][C:2]1[N:3]=[C:4]([OH:11])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1nc(F)cnc1C(N)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ncc(F)nc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.1 %

Procedure:
In a nitrogen atmosphere, 0.09 g of 5-fluoro-3-methoxy-2-pyrazinecarboxamide is suspended in 3.6 mL of acetonitrile. Then, 0.16 g of sodium iodide and 0.11 g of chlorotrimethylsilane are successively added to the suspension, which is then stirred at ambient temperature for 20 hours. Then, 2 mL of water and 40 mL of chloroform are added to the reaction mixture and separated into layers. The organic layer is separated, washed successively with 5% (w/v) aqueous solution of magnesium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform) to obtain 0.01 g of 5-fluoro-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: CSC.B.[N+:5]([CH2:8][C:9]1([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O-:7])=[O:6].CO.Cl>C1(C)C=CC=CC=1.O1CCOCC1>[N+:5]([CH2:8][C:9]1([CH2:15][CH2:16][NH2:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O-:7])=[O:6]
Reactant: N#CCC1(C[N+](=O)[O-])CCCCC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: Cc1ccccc1
Product: NCCC1(C[N+](=O)[O-])CCCCC1
Temperature: 60 °C
Yield: 56.1 %

Procedure:
Borane methyl sulphide (2.0 M in toluene, 1.3 mL, 2.6 mmol) was added to compound 3 (0.4 g, 2.2 mmol) in toluene (10 mL) under nitrogen. After heating to 60° C. for 3 hours, the mixture was allowed to cool, and 15 mL methanol was added followed by 15 mL 4 M HCl in dioxane. After reflux for 1 hour, the mixture was evaporated to dryness. Crystallization from ethyl acetate gave the required product as colorless crystals (0.23 g, 47%); mp 170–173° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.Br[C:37]1[CH:38]=[C:39]([CH2:43][C:44]([C:46]2[O:47][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)=[O:45])[CH:40]=[CH:41][CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:41]1[CH:42]=[CH:37][CH:38]=[C:39]([CH2:43][C:44](=[O:45])[C:46]2[O:47][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)[CH:40]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
Tri(o-toly)phosphine (25 mg, 0.082 mmol) and palladium(II) acetate (9 mg, 0.041 mmol) in acetonitrile (1 mL) was added to a mixture of methyl acrylate (84 mg, 0.98 mmol) and triethylamine (329 mg, 3.26 mmol). Aryl bromide (25) (278 mg, 0.82 mmol) in acetonitrile (3 mL) was then added and the reaction mixture heated in a CEM Discover microwave for 45 minutes at 90° C. The solvent was concentrated in vacuo, and the crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge eluting with 5-17% EtOAc in heptane. Yield: 222 mg, 78%; LC-MS tr 1.62 min; HPLC Purity: 100%; MS (ES+) m/z 347 (M+H)
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:30][C:31]1[CH:47]=[CH:46][C:34]([CH:35]=[CH:36][CH2:37][N:38]2[CH2:43][CH2:42][C:41](=O)[CH:40]([CH3:45])[CH2:39]2)=[CH:33][CH:32]=1.CC1C(=O)CCNC1.ClC1C=CC(C=CCCl)=CC=1>O1CCCC1.O>[Cl:30][C:31]1[CH:47]=[CH:46][C:34]([CH:35]=[CH:36][CH2:37][N:38]2[CH2:43][CH2:42][C:41](=[CH:8][O:9][CH3:10])[CH:40]([CH3:45])[CH2:39]2)=[CH:33][CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1CN(CC=Cc2ccc(Cl)cc2)CCC1=O
Agent: CC(C)(C)[O-]
Agent: CC1CNCCC1=O
Agent: ClCC=Cc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC=C1CCN(CC=Cc2ccc(Cl)cc2)CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (1.56 g) was added portionwise to a stirred suspension of methoxymethyltriphenylphosphonium chloride (4.76 g) in tetrahydrofuran (30 ml) at 0° C. under argon. The resulting orange mixture was stirred at 0° C. for 30 min., then 1-(4-chlorocinnamyl)-3-methyl-piperidin-4-one (1.83 g, prepared by alkylation of 3-methyl-piperidin-4-one [CAS No 5773-58-0] with 4-chloro-cinnamyl chloride) dissolved in a minimum volume of tetrahydrofuran was added dropwise and the resulting solution was stirred at room temperature for 1 hour, poured into water and extracted twice with ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 75:25) to afford 1-(4-chlorocinnamyl)-4-[1-methoxy-methylidene]-3-methyl-piperidine as a mixture of diastereoisomers. MS (ES+) 292/294 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Clc1nc(Cl)c2ccc(N3CCOCC3)cc2n1
Solvent: C1CCOC1
Product: Clc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
1.59 g (5.0 mmol) of 2,4-dichloro-7-morpholin-4-ylquinazoline were suspended in 50 ml of tetrahydrofuran, a solution of 1.24 ml (12.50 mmol) of piperidine in 20 ml of tetrahydrofuran was added at room temperature, and the mixture was stirred for 3 h. Conventional work-up gave 1.33 g of 2-chloro-7-morpholin-4-yl-4-piperidin-1-ylquinazoline (No. 2).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(Cl)(=O)C>N1C=CC=CC=1>[CH3:19][O:18][C:16]1[N:17]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=2)[CH:13]=[C:14]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:15]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNc2cc(-c3cccc(NC(C)=O)c3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine acetate [156 mg, 0.38 mmol, Example 2] in pyridine (1.3 mL) is added acetyl chloride (32 μL, 0.45 mmol). The reaction mixture is stirred for 3 hours at ambient temperature, quenched with the addition of water (20 mL), and extracted three times with EtOAc (20 mL). The combined extracts are washed four times with aqueous copper sulfate solution (10 mL), with water (10 mL), with brine (10 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica gel (4.5 g) eluting with 3% MeOH in DCM to afford N-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetamide [51 mg, 34%, Example 6(b)]. LCMS: RT=2.3 minutes, MS: 393 (M+H).