Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.S(Cl)([Cl:16])=O>>[CH:1]1([C:11]([Cl:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)C1C=CCc2ccccc21
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1C=CCc2ccccc21

Procedure:
In an example of this reaction 1,4-dihydro-alpha-naphthoic acid is reacted with thionyl chloride at room temperature for 1-6 hours to obtain 1,4-dihydro-alpha-naphthoic chloride. This compound is then reacted with an amine of the formula (3) and triethylamine in ether solvent under reflux for 0.1-3 hours to obtain a compound of the formula (1a). Compounds of the formulae (1b) and (1c) may also be produced in the same manner as just described using 3,4-dihydro-alpha-naphthoic acid and 1,2,3,4-tetrahydro-alpha-naphthoic acid, respectively as starting materials.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.Cl>CS(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Cl
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of hydroquinone (276.4 mg, 2.510 mmol) in anhydrous 3.64 mmol) and heated under a nitrogen atmosphere at 120° for 30 minutes. A solution of 4-(3-Bromo-benzyloxy)-1-chloro-2-nitro-benzene (from Example 15A) (774 mg, 2.259 mmol) in dimethylsulfoxide (4 mL) was added dropwise from an addition funnel over a period of 30 minutes at 120°, the mixture was then stirred at this temperature for 1 hour. The reaction was cooled in an ice bath, then poured into ice water (20 mL) and adjusted the pH to 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl ether (3×100 mL), the combined ethereal extracts were washed with water (3×100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation under vacuum. Purification of the residue by silica gel flash chromatography using 3% ethyl acetate/methylene chloride as eluent afforded the title compound as a dark yellow solid (386 mg, 0.927 mmol, 41%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:22]=[C:21]2[C:12]([C@@:13]3([CH2:31][CH3:32])[C@H:18]([CH2:19][CH2:20]2)[CH2:17][C@:16]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)([OH:23])[C@@H:15]([OH:30])[CH2:14]3)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:31]([C@:13]12[C:12]3[C:21](=[CH:22][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19][C@@H:18]1[CH2:17][C@:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)([OH:23])[C@@H:15]([OH:30])[CH2:14]2)[CH3:32]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@]12C[C@H](O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,3S,4aR,10aR)-7-(tert-butyl-dimethylsilanyloxy)-4a-ethyl-2-(pyridin-3-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3-diol (13 mg, 0.03 mmol) and acetic acid (0.05 mL, 0.87 mmol) in tetrahydrofuran (2 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.13 mL, 0.13 mmol). The mixture was stirred overnight at room temperature and the concentrated under vacuum. The residue was taken up in ethyl acetate and filtered through a plug of silica gel. The title compound, a solid (4.2 mg, 43%) was obtained by evaporation of the solvent. 1H NMR (CDCl3) selected signals: δ 9.00 (br s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.26 (d, J=5.7 Hz, 1H), 7.32 (dd, J=5.7, 7.8 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.65 (dd, J=2.6, 8.3 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 4.23 (dd, J=4.7, 13.0 Hz, 1H). MS: m/e 340 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=C[C:7]([C:8](O)=O)=[CH:6][CH:5]=1.CCCC([O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br)=[O:23])CC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:3]([O:2][C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH2:21][OH:20])=[CH:29][CH:28]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCC(CC)OCC(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)CO)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 45 %

Procedure:
To a solution of terephthalic acid monomethyl ester (1.0 g, 5.6 mmol) and 4-hexyloxy-2′-bromoacetophenone (synthesized by following (2.0 g, 6.7 mmol) in DMF (10 mL) was added K2CO3 (0.77 g, 5.6 mmol) and heated at 60° C. After 10 h, the reaction mixture was cooled to room temperature and poured into water. The product was extracted using EtOAc, washed with brine, dried and concentrated. The crude residue was purified by combiflash to afford 1.0 g (45%) product. 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H, J=7.0 Hz), 1.36-1.39 (m, 4H), 1.48-1.58 (m, 2H), 1.81-1.85 (m, 2H), 3.99 (s, 3H), 4.07 (t, 2H, J=6.5 Hz), 5.58 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.92 (d, 2H, J=9.0 Hz), 8.16 (d, 2H, J=9.0), 8.122 (d, 2H, J=9.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][C@@H:22]([N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1)[CH3:23]>>[CH3:19][O:20][CH2:21][C@@H:22]([N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1)[CH3:23]
Reactant: COC[C@H](C)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COC[C@H](C)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2—((S)-2-methoxy-1-methyl-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:28]#[C:29]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]#[N:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccnc1CN(CCCCNC#N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a 0° C. solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (237 mg, 0.80 mmol) in MeOH (10 mL) was added NaOAc (200 mg, 2.39 mmol) and cyanogen bromide (94 mg, 1.03 mmol) and stirred at room temperature for 17 hours. Water (10 mL) was added and the reaction mixture was extracted with CH2Cl2 (4×40 mL). The extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide pure COMPOUND 198 as a beige solid (190 mg, 74%). 1H NMR (CDCl3) δ 1.45-1.51 (m, 2H), 1.65-1.63 (m, 2H), 2.12 (s, 6H), 2.61-2.65 (m, 2H), 2.83-2.89 (m, 2H), 3.68 (s, 4H), 7.08 (dd, 2H, J=4.2, 7.8 Hz), 7.38 (d, 2H, J=7.8 Hz), 7.57 (br s, 1H), 8.37 (d, 2H, J=4.2 Hz). 3C NMR (CDCl3) δ 18.5, 21.1, 28.3, 44.4, 53.6, 58.2, 118.9, 122.9, 133.4, 138.6, 146.6, 156.7. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.0.4 CH2Cl2O.0.1CH40: C, 64.95; H, 7.32; N, 19.42. Found: C, 64.65; H, 7.22; N, 19.27.
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2].[H][H]>C(O)C.[Pd].C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: Cn1c(-c2cccnc2)c(CCCCCC=CC(=O)O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2cccnc2)c(CCCCCCCC(=O)O)c2ccccc21

Procedure:
3-(7-Carboxyhept-6-enyl)-2-(3-pyridyl)-1-methylindole (100 mg) is dissolved in 10 ml of absolute ethanol with a catalytic amount of 10% palladium of charcoal and hydrogenated at 1 atmosphere pressure. After 1 mole of hydrogen is consumed, the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated in vacuo to yield 3-(7-carboxyheptyl)-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(OC([N:49]1[CH2:52][CH:51]([C:53](O)=[O:54])[CH2:50]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:49]1[CH2:52][CH:51]([C:53]([N:22]2[CH2:21][CH2:20][CH:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][C:9]([NH:8][C:5]5[N:4]=[C:3]([NH:29][C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=5)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=4)[C:15]3=[O:18])[CH2:24][CH2:23]2)=[O:54])[CH2:50]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)C3CNC3)CC1)C2
Reaction time: 1 h

Procedure:
To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one C (41 mg, 0.07 mmol) in DMF (1.0 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (14 mg, 0.07 mmol), HATU (39 mg, 0.104 mmol), and DIEA (0.138 mmol, 24 μL) sequentially. The reaction mixture was stirred for 1 h, then partitioned between EtOAc and water. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) at room temperature for 1 h. The resulting solution was concentrated and then purified by preparative RP-HPLC to afford 2-(1-(azetidine-3-carbonyl)piperidin-4-yl)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenyl-amino)pyrimidin-2-ylamino)-5-isopropoxyisoindolin-1-one.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl.C(Cl)(=O)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:28]([O:29][CH3:30])=[O:31])=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(F)cc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.9 %

Procedure:
Methyl 2-(4-fluorobenzyl)piperidine-4-carboxylate (4.981 g, 19.82 mmol) was dissolved in DCM (150 mL) and DIPEA (4.14 mL, 23.79 mmol), then methyl carbonochloridate (1.873 mL, 23.79 mmol) was added. The solution was stirred at room temperature for 50 min. More methyl carbonochloridate (a few drops) were added and the reaction continued at room temperature for 1 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (5.82 g, 95%) as a yellow oil. MS m/z 310 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(O)cccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1COc2cccc(O)c2N1
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A stirred solution of 2-aminobenzene-1,3-diol (2.0 g, 16.0 mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous DMF (30 mL) was treated with 2-chloroacetyl chloride (1.81 g, 16.0 mmol) and stirring continued for 16 h at room temperature, then K2CO3 (2.65 g, 19.2 mmol) was added and the mixture further stirred for 16 h at the same temperature. The reaction mixture was diluted with DCM (100 mL), washed twice with water and then with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatographic column of silicagel to give desired product (1.7 g, 64% yield) LCMS (m/z): 166.1 [M+1]+.
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)O)cc1
Reaction time: 3 h
Yield: 55 %

Procedure:
11.3 g of D-panthenol (0.055 mol) are placed in 100 ml of THF while gassing with argon in a 500 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 27.8 g of 4-methoxycinnamic acid chloride (0.14 mol) in 100 ml of tetrahydrofuran is then added dropwise within about 15 minutes. A solution of 11.1 g of pyridine (0.14 mol) is now added dropwise within about 30 minutes and the mixture is stirred for a further 3 hours. The precipitate is filtered off under suction and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 300 ml of CH2Cl2. This solution is washed with 2× 60 ml of 5% HCl and then with 2× 60 ml of 5% NaHCO3. After drying (Na2SO4) the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (33.8 g) is chromatographed (toluene/ethyl acetate, 8:2) on 1 kg of silica gel (0.04-0.063 mm) under 0.5 bar pressure. There are obtained 15.9 g of yellowish <R>-panthenol diester of p-methoxycinnamic acid (yield 55%).
Reaction SMILES: [CH2:1]([S:17][CH2:18][C:19]1([CH2:24]O)[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:46])CCCCCCCCCCCCCCC>>[NH2:46][CH2:24][C:19]1([CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCCCCCCCCCCCCCSCC1(CO)CCCO1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Product: CCCCCCCCCCCCCCCCSCC1(CN)CCCO1

Procedure:
2-Hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran IVb1 is allowed to react and worked by the same procedure as described in (3), the summary of the experimental condition and the physical data of the prodcut are listed in the Tables 5 and 6.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N+:8]([C:7]1[C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (20 g, 126.15 mmol) in 1, 4 dioxane (378 mL) was added tributyl vinyl tin (48 g, 151.38 mmol). The reaction mixture was degassed using nitrogen for 30 min. Bis-(triphenylphosphin)palladium(II)-chloride (4.4 g, 6.3 mmol) was added to the reaction mixture. Reaction mass was stirred at 110° C. for overnight. The reaction mixture was cooled to rt. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-5% EtOAc in hexane to give 3-nitro-2-vinylpyridine: 1H NMR (400 MHz, DMSO-d6) δ 5.741 (dd, J=2.0 Hz, J=10.4 Hz, 1H), 6.536 (dd, J=2.4 Hz, J=16.8 Hz, 1H), 7.134-7.202 (m, 1H), 7.593 (dd, J=4.4 Hz, J=8.4 Hz, 1H), 8.388 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 8.857 (dd, J=0.8 Hz, J=4.4 Hz, 1H); LC-MS (ESI) m/z 151.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:13]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:13]=2[N:21]=1
Reactant: CN1CCC(O)CC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825 mmol) in DMF (2.500 ml) was added NaH (0.041 g, 55% dispersion in mineral oil, 0.945 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C., followed by the addition of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.15 g, 0.750 mmol). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (0.09 g, 43%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.12 (2H, m), 2.17-2.21 (2H, m), 2.22-2.32 (2H, m), 2.34 (3H, s), 2.84-2.89 (2H, m), 5.38-5.45 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: Br[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]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:25]4[CH:24]=[N:23][C:22]([NH2:21])=[N:27][CH:26]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.28 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.04 g, 13%). MS (ISP) 364.0 [(M+H)+]; mp 264-266° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8](O)=[O:9])[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][NH:47][C:48](=[O:59])[C@H:49]([NH:57][CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:16]([O:15][C:13](=[O:14])[N:11]([C@@H:7]([C:8](=[O:9])[N:57]([CH3:58])[C@@H:49]([C:48](=[O:59])[NH:47][CH3:46])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:6][C:4]1[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[S:1][CH:5]=1)[CH3:12])([CH3:17])([CH3:19])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1csc2ccccc12)C(=O)O
Reactant: CNC(=O)[C@@H](Cc1ccccc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
(2R)-3-(Benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonyl-methylamino)propionic acid (2.00 g; 5.96 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.81 g; 5.96 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.26 g; 6.56 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-phenylpropionamide (1.15 g; 5.96 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (1.02 mL; 5.96 mmol) were added. The reaction mixture was stirred for 48 hours. Methylene chloride (10 mL) was added. The reaction was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.89 g of ((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl carbamic acid tert-butylester.
Reaction SMILES: [N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:24][CH:25]([CH2:37][CH2:38][CH3:39])[C@@H:26]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)[OH:27]>>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:26]([C@@H:25]([NH:24][C:10](=[O:12])[CH:9]([CH2:13][CH:14]1[CH2:16][CH:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:23])[CH2:37][CH2:38][CH3:39])=[O:27]
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1
Product: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using 4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[Cl:13][C:14]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][C:18]=1[F:26].Cl>C1COCC1>[C:7]([CH:9]([C:24](=[S:25])[NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:14]=2[Cl:13])=[C:18]([F:26])[CH:19]=1)[C:10]([NH2:12])=[O:11])#[N:8]
Reactant: Fc1cc(N=C=S)ccc1Oc1cc(Cl)ccc1Cl
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(C(N)=O)C(=S)Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 5 °C
Yield: 82.5 %

Procedure:
To a solution of potassium tert-butoxide (0.6 g, 5.36 mmol) in 10 ml of anhydrous THF was added 2-cyanoacetamide (0.45 g, 5.36 mmol) under argon. The mixture was cooled to 5° C. and added dropwise to a solution of 4-(2,5-dichloro-phenoxy)-3-fluoro-phenylisothiocyanate (1.53 g, 4.87 mmol) in 5 ml of dry THF with stirring under argon. After 15 min of stirring at 5° C., this reaction mixture was warmed to room temperature and stirred for another 2 h. The reaction mixture was poured into 200 ml of ice water with stirring and acidified with 10% HCl. The solid was filtered and washed with water. After drying in vacuo, the crude product (1.6 g, 82.5%) was obtained in sufficient purity for the next step.