Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[OH:50][C:51]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:52]=1[CH2:53][NH2:54]>CN(C)C=O.CN(C1C=CN=CC=1)C>[F:59][C:57]1[CH:56]=[CH:55][C:52]([CH2:53][NH:54][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:51]([OH:50])[CH:58]=1
Reactant: NCc1ccc(F)cc1O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1O)c(OCc1ccccc1)c2=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
A solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid, (1.50 g, 4.54 mmol) and HATU (2.07 g, 5.45 mmol) in anhydrous dimethylformamide was stirred for 20 minutes under a nitrogen atmosphere at room temperature. To the solution was added intermediate 135, 2-hydroxy-4-fluoro-benzylamine hydrochloride, (1.05 g, 5.9 mmol) followed by DMAP (1.39 g, 11.4 mmol), and the reaction mixture stirred at 60° C. for 90 minutes. The solvent was removed in vacuo and the crude residue purified by flash column chromatography (SiO2), eluting with 40%-60% ethyl acetate in hexanes to give the title compound (1.31 g, 64% yield) as a solid. 1H NMR (500 MHz, CDCl3) δ ppm: 9.69 (1H, br s), 8.18 (1H, t, J=6.3 Hz), 7.44 (2H, dd, J=6.6, 2.6 Hz), 7.30-7.35 (3H, m), 7.00 (1H, dd, J=8.2, 6.7 Hz), 6.68 (1H, dd, J=10.4, 2.4 Hz), 6.54 (1H, dt, J=8.2, 2.4 Hz), 5.29 (2H, s), 4.36 (2H, d, J=6.7 Hz), 3.97-4.05 (4H, m), 1.61 (6H, s).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:65]2[CH2:66][CH2:67][CH:62]([OH:61])[CH2:63][CH2:64]2)=[O:24])=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OC1CCNCC1
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: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(O)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Hydroxypiperidine (43.9 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (51 mg, 98% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32](O)=[O:33])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:63]([O:70][C:71](=[O:77])[C@@H:72]1[CH2:76][CH2:75][CH2:74][NH:73]1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:73]3[CH2:74][CH2:75][CH2:76][C@H:72]3[C:71]([O:70][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:77])=[O:33])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3cccc(F)c3)n2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.000 g 4-((S)-3-tert-Butoxycarbonyl-2-{[5-carboxymethoxy-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.518 g HOBt, 1.2 ml DIPEA and 0.817 g L-proline benzyl ester hydrochloride at RT. Then 0.648 g EDC was added portionwise and the suspension stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 2.5 g.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc2ccccc12
Temperature: 80 °C
Yield: 88.8 %

Procedure:
Under an argon atmosphere, 50 g (0.241 mol) of 1-bromonaphthalene, 2.5 g (3.6 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 0.68 g (3.6 mmol) of copper Iodide were dissolved in 500 ml of diisopropylamine in a 1 L 3-necked flask equipped with a stirrer, thermometer and reflux condenser. 35.6 g (0.362 mol) of trimethylsilyl acetylene was slowly dropped into the resulting mixture at room temperature. The reaction mixture was slowly heated to 80° C. and refluxed 12 hours. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated salt was filtered off, and the solvent was removed from the filtrate under a reduced pressure. The residue was dissolved in methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed, to obtain a liquid. The obtained liquid was purified by silica gel column chromatography using hexane as an eluent, to give a colorless viscous liquid. The liquid was recrystallized from ethanol to give white crystal in needle-shape. The white crystal was recovered and then sufficiently dried at room temperature, to give 48 g (88.9% yield) of the desired product having a melting point of 41-43° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](OS(C)(=O)=O)[CH3:13])=[C:8]([I:19])[CH:7]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.C(Cl)(Cl)Cl>[N:1]([CH:12]([C:9]1[C:8]([I:19])=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13])=[N+:2]=[N-:3]
Reactant: CC(OS(C)(=O)=O)c1cnc(F)cc1I
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.3 %

Procedure:
Add sodium azide (0.45 g, 7 mmol) and tetra-N-butylammonium bromide (0.12 g, 0.4 mmol) to a solution of methanesulfonic acid 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl ester (1.2 g, 3.5 mmol) in DMF (20 mL) at 0° C. Stir the mixture at RT for 42 h. Dilute the reaction mixture with chloroform. Wash the organic phase with water and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a white solid (0.77 g, 76%). 1H NMR (400 MHz-CDCl3) δ 1.56 (d, J=6.8 Hz, 1H), 4.90 (m, 1H), 7.45 (d, J=3.2 Hz, 1H), 8.17 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[CH3:14][O:15][CH2:16]Cl>CN(C=O)C.O>[CH3:14][O:15][CH2:16][O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a suspension of 5.0 g of NaH (208.33 mmol) in 150 mL of DMF under argon flow were added 20.0 g of solid 2-hydroxynaphthalene (138.7 mmol) at a temperature of 0° C., by small portions. The suspension was kept under stirring for 4 h at room temperature, 17.8 g of methoxymethyl chloride (221.2 mmol) were added slowly, and the reaction mixture was stirred for 10 additional hours. The reaction was carefully diluted with 1 L of water and the organic part was extracted with 3 times 50 mL of CH2Cl2. The combined organic extracts were washed twice with 500 mL of water, brine and dried over MgSO4. The solution was evaporated, dried in vacuum at a temperature of 80° C. to give 25.1 g of colorless oily product (133.3 mmol) that was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:10][CH2:11]1)[CH3:5])=[O:54]
Reactant: Cc1ccnc(Cl)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (0.077 g, 0.20 mmol), EDCI (0.043 g, 0.22 mmol) and HOBT (0.030 g, 0.22 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.038 g, 0.22 mmol) followed by DIPEA (42 μL, 0.24 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.062 g, 57%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.06 (m, 1H), 1.22 (m, 1H), 1.57 (m, 2H), 1.81 (m, 3H), 2.11 (br t, 1H), 2.36 (s, 6H), 2.53 (br t, 1H), 2.75-2.88 (m, 3H), 3.20-3.33 (m, 2H), 3.71 (s, 3H), 3.82 (m, 1H), 3.90 (m, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.98 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=3.0 Hz), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 18.9, 19.1, 29.6, 30.4, 30.9, 39.9, 43.8, 47.0, 51.9, 55.5, 59.2, 60.0, 114.4, 119.9, 124.2, 125.1, 148.0, 149.0, 149.3. ES-MS m/z 536 (M+H), 558 (M+Na). Anal. Calcd. for C30H38N5O2Cl.0.2 CH2Cl2: C, 65.58; H, 7.00; N, 12.66. Found: C, 65.64; H, 7.15; N, 12.79.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:12][C:13]([OH:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC(N)=O
Product: Oc1nc(O)c2ccc(F)cc2n1
Temperature: 160 °C
Yield: 89.5 %

Procedure:
A mixture of 2-amino-4-fluorobenzoic acid (25.3 g) and urea (48.9 g) was gradually added to a flask heated at 160° C. and then heated to 245° C. over 30 min. Light yellow solids were precipitated. The reaction mixture was cooled to room temperature, then methanol (250 mL) was added to the reaction mixture, the mixture was heated to reflux for 30 min, the solids were washed and cooled to room temperature, and then the precipitated solids were collected by filtration. The resulting solids were washed again with methanol (300 mL) to obtain 7-fluoroquinazoline-2,4-diol (26.3 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 60 °C
Yield: 162.7 %

Procedure:
A mixture of 5-bromo-2-hydroxy acetophenone (1.00 g, 4.65 mmol), 4-(trifluoromethyl)phenylboronic acid (1.32 g, 6.97 mmol), potassium carbonate (1.30 g, 9.38 mmol), tetrakis(triphenylphosphine)palladium (0) (538 mg, 0.465 mmol) in 1,4-dioxane (30.0 mL) and water (18.0 mL) was heated to 60° C. for 18 hours under nitrogen. The reaction was allowed to cool to room temperature and concentrated in vacuo to afford a dark brown oil which was dissolved in ethyl acetate (50 mL) and filtered through Arbocel™. The Arbocel™ was washed with ethyl acetate (100 mL). The combined organics were washed sequentially with a 0.5M aqueous solution of hydrogen chloride (2×50 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (2.12 g). The oil was then purified by silica gel column chromatography (5%-10% ethyl acetate in heptane gradient elution) to afford the title compound as a yellow solid (795 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:30][N:31]([CH:33]=O)[CH3:32]>C(Cl)Cl>[C:4]([C:3]1[CH:9]=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:12][C:2]=1[N:1]=[CH:30][N:31]([CH3:33])[CH3:32])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N=CN(C)C
Temperature: 55 °C

Procedure:
To a stirred solution of 15.7 g (50 mmol) of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (Pfizer patent WO 96130347) in 50 ml of DMF at 0° C. was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55° C. for 45 m, cooled, diluted with methylene chloride, and treated at 0° C. with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0° C. with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) δ 3.02 (s, Me2N).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]([CH2:31][C:32](O)=[O:33])[CH3:30])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.C(OCC)C.CO.CCCCCC>[C:22]([O:26][C:27](=[O:28])[N:29]([CH3:30])[CH2:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CN(CC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)C(=O)OC(C)(C)C
Yield: 96.9 %

Procedure:
Preparation of example 19 from the title compound of Example 7 (hydrochloride) (18 mg, 0.065 mmol), (tert-butoxycarbonyl-methyl-amino)-acetic acid (12 mg, 0.065 mmol), triethylamine (0.012 mL, 0.085 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.072 mmol) in CH2Cl2 (0.5 mL) and N,N-dimethylformamide (0.5 mL) was carried out analogously to Example 11. Silica gel chromatography (10:9:1 hexane:CH2Cl2:methanol), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (28 mg, 0.063 mmol) as a yellow powder in 96% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2cccc3c2CNCC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C

Procedure:
A solution of 4.2 parts of 8-phenyl-1,2,3,4-tetrahydroisoquinoline and 4 parts of triethylamine in 90 parts by volume of methylene chloride is cooled in an ice bath with stirring and 1.7 part of acetyl chloride in 10 parts by volume of methylene chloride is added slowly. The mixture is allowed to warm to ambient temperature and stirred for about 2 hours. The reaction solution is washed four times with 20 parts by volume portions of water and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to afford 2-acetyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)([O-])=O>[Pd]>[NH2:5][C:8]1[C:9]([CH2:2][CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2
Reactant: CC[Mg+]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: [Br-]
Product: CCc1c(N)ccc2[nH]ccc12

Procedure:
Addition of EtMgBr to 5-nitroindole followed by hydrogenation over Pd/C provided 5-amino-4-ethylindole.
Reaction SMILES: OC1C=CC(N2CCN(C3C=CC([N:20]4[CH:24]=[N:23][N:22]([C@@H:25]([CH3:28])[CH2:26][CH3:27])[C:21]4=[O:29])=CC=3)CC2)=CC=1.[OH-].[Na+].CN(C)C=O>O>[CH3:28][CH:25]([N:22]1[C:21](=[O:29])[NH:20][CH:24]=[N:23]1)[CH2:26][CH3:27]
Reactant: CC[C@H](C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)n1nc[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6.7 g of (+)-(2R,cis)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolane-4-methanol 4-methylbenzenesulfonate(ester) 4-methyl-benzenesulfonate(salt 1:1) (intermediate (10)), 3.9 g of (+)-(S)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (intermediate (7)), 1.5 g of sodium hydroxide flakes and 100 ml of N,N-dimethylformamide was stirred overnight at 50° C. under a nitrogen atmosphere. After cooling, water was added to the reaction mixture. The precipitate was filtered off and taken up in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was triturated with methanol, yielding 5.6 g (83.2%) of (+)-[2R-[2α,4α,4(S)]]-4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 182.4° C.; [α]D20=+14.130° (c=1% in methanol) (comp. 8).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH:6]=1.[C-:17]#[N:18].[Na+].O>CS(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][C:17]#[N:18])=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)C(CCCBr)=CCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CCCC#N)=CCC2
Yield: 93 %

Procedure:
A mixture of 4-(3-bromopropyl)-1,2-dihydro-6-methoxynaphthalene (10 g, 35.6 mmol.) and sodium cyanide (1.92 g, 39.1 mmol.) was stirred in dimethyl sulfoxide (20 ml) for one hour at room temperature. The reaction mixture was poured into water, then the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue thus obtained was purified by means of a silica gel column chromatography (ethyl acetate:hexane=1:9) to afford the titled compound. (7.5 g, yield 93%, oily).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.CC[O:24]CC>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCc1ccccc1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-phenylbutyronitrile (21.7 g, 0.12 mole) in ether (400 ml) at 78° C. is added 85 ml. of 25.3% diisobutylaluminum hydride in toluene over a period of 1 hour. After an additional 1 hour, the dry ice-acetone bath is removed and the reaction mixture is stirred at ambient temperature for 3 hours. The reaction mixture is added slowly to 5% aqueous sulfuric acid and then is extracted with several portions of ether. The ether extracts are combined, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the ether, the residual yellow oil is distilled in vacuo to give an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:17](O)=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)=[O:18]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc(-c2ccccc2)cc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)cc2ccccc12

Procedure:
The procedure of Example 20 is followed using 3-phenylnaphthalene-1-carboxylic acid (4.3 g), thionyl chloride (20 ml) and N-methylbut-2-ylamine (1.5 g) in pyridine (20 ml) as the starting materials. After recrystallisation from petroleum ether, N-methyl-N-(1-methylpropyl)-3-phenylnaphthalene-1-carboxamide (2.8 g), melting at 125° C., is obtained.