Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:61])[CH3:60])[CH2:53][CH2:52]2)=[CH:47][CH:46]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:52][CH2:53][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:60])[CH3:61])[CH2:55][CH2:56]4)=[CH:47][CH:46]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN(C)C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20.5 mg, 0.050 mmol) and 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone di-TFA salt (24 mg g, 0.050 mmol) were combined in i-PrOH (1 mL) and TEA (10.6 mg, 0.11 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/1120 gradient over 10 min) and lyophilized to provide 24 mg (80%) of 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.31 (s, 1H), 9.10 (br s, 1H), 8.48 (s, 1H), 7.51 (d, 2H, J=8.1 Hz), 7.22-7.34 (2H), 7.13-7.16 (m 3H), 4.38 (q, 2H, J=7.0 Hz), 3.09 (br s, 2H), 2.95-3.02 (m, 6H), 2.71-2.80 (m, 2H), 2.39 (s, 6H), 2.11-2.22 (m, 2H), 1.55-1.93 (m, 4H), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:16]([F:15])=[CH:17][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)cc3)nc2n(CC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.31 g (13.9 mmol) of 4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.00 g (yield 51%) of Compound 149 as colorless columns.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@@H]1CCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[C@@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (xi), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester, by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester with (R)-(−)-2-methylpyrrolidine (obtained from Advanced Asymmetrics).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:15][C:4]1[N:3]=[C:2]2[NH:17][N:18]=[C:8]([C:10]3[NH:11][CH:12]=[CH:13][CH:14]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: O=C(c1ccc[nH]1)c1ccc(Cl)nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(-c3ccc[nH]3)n[nH]c2n1
Temperature: 90 °C

Procedure:
A mixture of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (1.8 g) and hydrazine hydrate (0.5 mL) in ethanol (70 mL) was heated at 90° C. for 20 hours. The reaction was concentrated to 40 mL, diluted with water (5 mL) and cooled. The precipitate was collected and dried to give 0.84 g of the titled compound.
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([O-:23])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][C:53]=1[C:65]([F:68])([F:67])[F:66])([O-:51])=[O:50].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([N:62]3[CH2:63][CH2:64][CH:59]([NH:58][C:55]4[CH:56]=[CH:57][C:52]([N+:49]([O-:51])=[O:50])=[C:53]([C:65]([F:66])([F:67])[F:68])[CH:54]=4)[CH2:60][CH2:61]3)=[O:23])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CCC(CCCC(=O)[O-])CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2CCC(CCCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of 4-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-butyric acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 136) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stirring is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (14 mg; 0.023 mmol). The structure was confirmed using Protocol I-D. Calculated mass=575; observed mass=575; HPLC retention time=1.70 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([S:13]([O-:15])=[O:14])[CH2:11][CH3:12].[Na+].C(OCC)(=O)C>CS(C)=O.CCCCCC>[CH2:10]([S:13]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCS(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCCS(=O)(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
4-Fluorobenzaldehyde (3.03 mL, 28.2 mmol) and sodium n-propylsulphinate (4.03 g, 31.0 mmol, synthesised as described in J. Med. Chem. 1989, 32, 2436) were dissolved in dry DMSO and the resulting solution heated at 100° C. for 18 h. The mixture was allowed to cool and then poured onto approximately 50 g of ice. After the ice had melted, the product was extracted into ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated. Chromatography on silica eluting with 20 to 40% ethyl acetate in hexane afforded the product as a white solid (3.21 g, 54% yield). 1H NMR (400 MHz, CDCl3) 1.02 (3H, t, J=7.5 Hz), 1.72-1.82 (2H, m), 3.10-3.14 (2H, m), 8.07-8.11 (4H, m), 10.14 (1H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[C:33]([O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])([CH3:40])[CH3:39])[CH3:38]
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}-2-methylpropionic acid ethyl ester, 1H NMR (400 MHz, CDCl3), δ8.04 (d, J=8.3 Hz, 2H), 7.65 (dd, J=11.0, 8.1 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 6.64-6.57 (m, 2H), 4.27-4.17 (m, 4H), 2.96 (t, J=6.8 Hz, 2H), 2.54 (t, J=7.1 Hz, 2H), 2.38 (s, 3H), 1.59 (quintet, 7.6 Hz, 2H), 1.53 (s, 6H), 1.26 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), MS (ES) m/e 528 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCOCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[S:26]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])=[O:28]
Reactant: Nc1ccccc1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 8 h

Procedure:
Aniline hydrochloride (64.8 mg, 0.05 mmol) is dissolved in 1,4-dioxane (1 ml) in a reaction tube and Na2CO3(85 mg) dissolved in water (0.5 ml) is added. To this mixture is added 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (115 mg, 0.43 mmol) (Intermediate A, prepared as described in WO03072557, page 77) in 1,4-dioxane (1 ml). The reaction mixture is left at room temperature overnight and monitored by LC-MS. The reaction mixture is shaken overnight with amino polystyrene (300 mg) and macroporous-isocyanate (300 mg), filtered and the resin is washed with MeOH (0.5 ml). The filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O.C(COC)OC>[C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Yield: 72.7 %

Procedure:
To a 1000 mL, 3-necked flask equipped with a stir bar, nitrogen inlet, and a reflux condenser were added 2,5-dibromopyridine (39.9 g, 84.2 mmol), 3-biphenylboronic acid (20.0 g, 101 mmol), palladium(H) acetate (0.47 g, 2.1 mmol), triphenylphosphine (2.2 g, 8.4 mmol), sodium carbonate (24.1 g, 227 mmol), dimethoxyethane (170 mL), and water (114 mL). The reaction mixture was heated at reflux for 16 h, after which ethyl acetate (200 mL) was added. The organic layer was then dried over magnesium sulfate and evaporated to dryness. Purification of the resulting solid on a silica gel column with ethyl acetate/hexane as the eluent yielded 19.0 g (73%) of 2-(biphenyl-3-yl)-5-bromopyridine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 38.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.34 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.42 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:23]=[CH:24][C:25]#[N:26])=[CH:5][C:4]=2[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]#[N:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: COCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon catalyst (200 mg), methanol (100 mL), and 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (925 mg, 2.63 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken at 50° C. for approximately 18 hours. The reaction mixture was cooled to ambient temperature and then filtered through a 0.2 micron PTFE membrane filter. The filtrate was concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL) to provide 760 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile as a white solid, mp 191-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.O[N:23]1C2C=CC=CC=2N=N1.C(OC(N1CCC(CN)CC1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH2:23])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCO3)cc1
Yield: 172.5 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), [1-(tert-butoxycarbonyl)piperidin-4-yl]methylamine (1393 mg, 6.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 ml) was added to the residue, and the resulting mixture was washed successively with water (10 ml×3), a 10% aqueous solution of potassium hydrogensulfate (10 ml×3), an aqueous saturated solution of sodium bicarbonate (10 ml×3) and an aqueous saturated solution of sodium chloride (10 ml). The organic layer was dried with anhydrous magnesium sulfate and then was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 80 g, ethyl acetate/hexane 1/2→1/1). The objective fractions were concentrated under reduced pressure to obtain N-[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (2409 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9](C)[C:10]2[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=2)[CH2:13][NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[O:8])=[CH:5][CH:4]=1.NC1C=CC([F:43])=C(C=1)C#N.COC1C=CC(C(O)=O)=CC=1>>[F:43][C:28]1[CH:29]=[CH:30][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:11][C:12]=1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Reactant: N#Cc1cc(N)ccc1F
Agent: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccc(F)c(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1

Procedure:
4-[2-Fluoro-5-(4-methoxy-benzoylamino)-benzylamino]-quinazoline-8-carboxylic acid amide was prepared according to example 4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid amide, starting from 5-Amino-2-fluoro-benzonitrile and 4-methoxy-benzoic acid:
Reaction SMILES: N[C:2]12[CH:17]([OH:18])[CH2:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH:17]([C:2]12[CH2:16][CH:9]([C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=31)[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NC12c3ccccc3C(CC1O)c1ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CC12CC(c3ccccc31)c1ccccc12
Reaction time: 5 h
Yield: 100.5 %

Procedure:
To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (3.0 g) in acetic acid (240 ml) was added a solution of sodium nitrite (6.7 g) in water (120 ml) at 2° - 5° C., and the resulting mixture was stirred at the same temperature for 1 hour and at 95° - 105° C. for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (2.8 g), which were recrystallized to give colorless crystals (2.45 g), M.P. 99° - 100° C. Further, purification by recrystallization gave analytically pure 9-formyl-9,10-dihydro-9,10-methanoanthracene, M.P. 102.5° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15].[CH3:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)[CH:23]=[C:22]([CH3:38])[C:21]=1O>ClCCl>[O:15]=[C:14]([CH3:16])[C:13]([O:18][C:21]1[C:22]([CH3:38])=[CH:23][C:24]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:28]=2)=[CH:25][C:20]=1[CH3:19])=[O:17]
Reactant: CC(=O)C(=O)O
Reactant: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1c(C)cc(Nc2ccn(-c3ccccc3)n2)cc1C
Reaction time: 16 h

Procedure:
1,1'-carbonyldiimidazole (4.9 g) was added batchwise to pyruvic acid (2.6 g) in dichloromethane (100 ml), and after 0.5 hours 2,6-dimethyl-4-(1-phenyl-1H-pyrazol-3-yl) aminophenol (2.8 g) was added. The mixture was left for 16 hours, then evaporated, and the residue was chromatographed (silica, dichloromethane) to give, after crystallisation (hexane/ethyl acetate), the title product (1.0 g) mp 123°-125°.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]([C:10]#[C:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:42][Si](C)(C)C(C)(C)C(C)C)[CH2:25][C@@H:26]2[O:34][Si](CC)(CC)CC)=[CH:21][CH:20]=3)[CH2:17][CH:16]=1)[CH3:14])([CH3:9])[CH3:8])(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.O>O1CCCC1>[CH3:8][C:7]([OH:6])([C:10]#[C:11][CH2:12][C@H:13]([C:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:42])[CH2:25][C@@H:26]2[OH:34])=[CH:21][CH:20]=3)[CH2:17][CH:16]=1)[CH3:14])[CH3:9]
Reactant: CC[Si](CC)(CC)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C(C)C)CC2=CC=C3[C@H](CC[C@]4(C)C([C@H](C)CC#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]34)[C@]21C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 40 h
Yield: 86.1 %

Procedure:
A mixture of 20.7 g (26.5 mmol) of (1α,3β)-[[25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]cholesta-5,7,16-trien-23-yn-1-yl]oxy]triethylsilane and 265 mL (265 mmol) of 1M Bu4NF in tetrahydrofuran was stirred at 30°-35° C. for 40 hr. After cooling to room temperature, 265 mL of EtOAc and 265 mL of water were added. The aqueous layer was extracted with 2×125 mL of EtOAc. The combined EtOAc solutions were concentrated to dryness. The residue was suspended in 130 mL of hexane and 130 mL of water, and the mixture was stirred for 30 min prior to filtration. The solid was washed with 130 mL of water and then with 130 mL of hexane. After being dried by suction, the solid was dissolved in 90 mL of hot methanol. After the solution was diluted with 45 mL of water and cooled to room temperature, the mixture was stored in a refrigerator overnight. The precipitate was filtered and washed with 100 mL of methanol-water (2:1). Drying at room temperature under high vacuum for 24 hr gave 9.37 g of (1α,3β)-cholesta-5,7,16-trien-23-yne-1,3,25-triol
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[F:15][C:16]([F:37])([S:33](F)(=[O:35])=[O:34])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1>[C:16]([S:33]([NH:7][CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:35])=[O:34])([C:17]([C:18]([C:19]([C:20]([C:21]([F:23])([F:24])[F:22])([F:25])[F:26])([F:28])[F:27])([F:30])[F:29])([F:32])[F:31])([F:37])[F:15]
Reactant: CN(C)CCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of dimethylaminopropylamine, H2NC3H6N(CH3)2 (12.2 g, 0.12 mole), triethylamine, (C2H5)3N (8.1 g, 0.08 mole) and toluene (60 g) was first prepared at ambient temperature and about atmospheric pressure in an inert atmosphere of nitrogen. To this mixture was added perfluorohexanesulfonyl fluoride, C6F13SO2F (41.0 g, 0.10 mole). The total mixture was then heated in a stainless steel reaction vessel at 90° C. for a period of about 3 hours forming a homogeneous reactant solution. During this period the aforementioned Reaction (a) takes place to produce intermediate N-[3-(N',N'-dimethylamino)propyl]perfluorohexane sulfonamide, C6F13SO2N(H)C3H6N(CH3)2.