Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH:24](O)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:6])=[O:25]
Reactant: Nc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=CNc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 91.7 %

Procedure:
0.26 g (0.000838 mol) of 1-benzyl-piperidin-4-yl 3-amino-benzoate was dissolved in 8.5 ml of toluene, treated with 0.84 ml (0.0222 mol) of formic acid and boiled at reflux for 12 hrs. The mixture was freed from solvent and the residue was taken up in ethyl acetate and washed with sat. carbonate solution and sodium chloride solution. It was dried over sodium sulfate. 0.26 g (92%) of 1-benzyl-piperidin-4-yl 3-formamido-benzoate was obtained as a brownish oil. MS: me/e=339 (C20H23N2 O3 +).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][C:13]1[C:14]2[N:21]=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][C:13]1[C:14]2[N:21]=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: COc1ccc(CCNc2ncnc3scnc23)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(CCNc2ncnc3scnc23)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
[2-(2-Fluoro-4-methoxy-phenyl)-ethyl]-thiazolo[5,4-d]pyrimidin-7-ylamine (204 mg, 0.67 mmol) was dissolved in CH2Cl2 (3.4 mL) in a 25 mL round bottom flask equipped with a magnetic stir bar, a septum and a dry nitrogen line. After cooling to 0° C., the solution was treated with 1.0 M boron tribromide (BBr3) solution in CH2Cl2 (3.4 mL), and the reaction mixture became brown. After stirring 3 h at 0° C., the mixture was treated with satd aq sodium bicarbonate (NaHCO3; 10 mL) and stirred at 0° C. for another hour. The precipitate was collected by suction filtration, washed with cold H2O (2×5 mL), and air dried on the filter to provide 3-fluoro-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]phenol (Compound 58; 127 mg) as a beige powder: mp 193° C.; 1H NMR (DMSO-d6) δ 9.64 (br s, 1H), 9.24 (s, 1H), 8.42 (br m, 2H), 7.07 (t, J=8.8 Hz, 1H), 6.53-6.49 (m, 2H), 3.71-3.66 (m, 2H), 2.85 (t, J=7.3 Hz, 2H); ESIMS: m/z 291.2 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42])[N:35]=[N:34]1>C(Cl)Cl>[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([Br:23])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:42])[N:35]=[N:34]1
Reactant: NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (92 mg, 0.220 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.077 mL, 0.441 mmol). 4-(1H-1,2,3-triazol-4-yl)butanoyl chloride (38.2 mg, 0.220 mmol) in DCM (2 mL) was added and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine, and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH/DCM as eluent to afford the title compound;
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1(O)C=CC=CC=1.[C:16](=[O:18])=[O:17]>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: O=C=O
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: O=C(O)c1ccc(O)cc1

Procedure:
In a pressure reaction vessel were charged 100 g of sodium phenolate, 35 g of phenol and 400 g of a mixture of hydrogenated triphenyls, and a reaction was allowed to proceed at 250° C. and at a carbon dioxide pressure of 7 kg/cm2 (G) for 20 minutes, with stirring The reaction mixture was cooled and charged into 200 ml of water, followed by separation into the reaction medium layer and the water layer at 60° C. The water layer was extracted with 50 g of xylene, and the phenol was recovered with an aqueous potassium hydroxide solution from the reaction medium and extraction medium layers. After recovery of phenol, the water layer was made acid with dilute sulfuric acid to give 80.8 g of p-hydroxybenzoic acid (having a purity of 100%), with neither salicylic acid nor isophthalic acid being detected as an isomer. The yield based on potassium phenolate was 77.3%, and the recovered phenol was 21.8 g, with the selectivity being 99.7%.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[C:6]([C:30]([F:33])([F:32])[F:31])[CH:5]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([O:42]CC)=[O:41])[CH2:35]1>CCO>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[C:6]([C:30]([F:32])([F:31])[F:33])[CH:5]=1)[CH2:3][N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1
Reactant: FC(F)(F)c1cc(C2CO2)ccc1-c1noc(-c2onc(-c3ccccc3)c2C(F)(F)F)n1
Reactant: CCOC(=O)[C@H]1CCCNC1
Solvent: CCO
Product: O=C(O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(C(F)(F)F)c2)C1
Temperature: 80 °C
Yield: 37.6 %

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)-2-(trifluoromethyl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (50 mg, 0.107 mmol) in EtOH (5 mL) was added (S)-ethyl piperidine-3-carboxylate (50.5 mg, 0.321 mmol). The reaction mixture was heated at 80° C. overnight and solvents were removed in vacuo. The mixture was treated with 6N HCl in MeCN at 50° C. for 24 h. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 24 mg of (3S)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 7.99-8.06 (1H, m), 7.91-7.96 (1H, m), 7.81-7.90 (1H, m), 7.59 (2H, d, J=6.59 Hz), 7.44-7.56 (3H, m), 3.69-4.04 (1H, m), 3.34-3.64 (3H, m), 3.26-3.35 (2H, m), 2.72-3.14 (2H, m), 2.00-2.22 (1H, m), 1.75-2.00 (2H, m), 1.56 (1H, t, J=12.81 Hz). MS (m+1)=597. HPLC Peak RT=3.4 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Mg]Cl)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][SiH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:27]([Si@H:24]1[CH2:23][CH2:22][C@H:21]([CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][CH:17]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: Fc1ccc(C#C[Mg]Cl)cc1
Reactant: CCC[SiH]1CCC(CCc2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCc2ccc(C#Cc3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml (30.0 mmol) of a tetrahydrofuran solution of 1.5M p-fluorophenylethynyl magnesium chloride was dripped into a mixture of 3.50 g (10.8 mmol) of 4-(2-(p-bromophenyl) ethyl)-1-n-propyl-1-silacyclohexane, 80 mg of tetrakis (triphenylphosphine) palladium (0) and 20 ml of tetrahydrofuran. The reaction mixture was stirred for 8 hours at room temperature. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 2.87 g (yield 73%) of the target product.
Reaction SMILES: Br[C:2]1[C:3]([CH3:33])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:39]1[N:43]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[N:42]=[CH:41][CH:40]=1)CCC>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:8](=[O:22])[N:6]3[CH:7]=[C:2]([C:39]4[N:43]([C:44]5[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=5)[N:42]=[CH:41][CH:40]=4)[C:3]([CH3:33])=[C:4]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[C:5]3=[N:10]2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1c(Br)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-2-(4-methanesulfonyl-benzyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Int. 16, 45 mg, 0.083 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 69 mg, 0.15 mmol) by a similar method to that used in Example 1 (Step 4) (24 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cc(F)cc(F)c1
Yield: 71.8 %

Procedure:
Using 0.21 g of 3,5-difluorobenzyl bromide, 3 ml of N,N-dimethyl-formamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.21 g of 2-(3,5-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (71)).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[O:14]S(C)(=O)=O.CS(C)=O.[OH-].[K+].Cl>CS(C)=O.O>[F:10][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]([OH:14])=[C:4]([CH:9]=1)[CH:3]=[O:2]
Reactant: COC(OC)c1cc(F)c([N+](=O)[O-])cc1OS(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a mixture of 0.348 g (1.13 mmole) of methanesulfonic acid 2-dimethoxymethyl-4-fluoro-5-nitro-phenyl ester (IV.46a) and 4 mL of dimethylsulfoxide, cooled briefly in an ice bath, was added dropwise a cold solution of 0.10 g of potassium hydroxide in 1 mL of dimethylsulfoxide-water (1:1). The resulting dark red mixture was stirred at room temperature for 15 minutes and then was made acidic by addition of 1 M hydrochloric acid to give a yellow mixture. The mixture was partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted three times with 25 mL of ethyl acetate. The combined organic layers were washed three times with 30 mL of water, once with 30 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.195 g of 5-fluoro-2-hydroxy-4-nitro-benzaldehyde (IV.46b) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)([CH3:13])=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:7]1[C:2]([NH:20][C@H:17]2[CH2:18][CH2:19][C@@H:14]([C:11]([CH3:13])=[CH2:12])[CH2:15][CH2:16]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: C=C(C)C1CCC(N)CC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Temperature: 25 °C

Procedure:
1.6 g (0.009 mol) of 4,5-dichloro-6-ethylpyrimidine and 1.2 g (0.009 mol) of 4-isopropenylcyclohexylamine were stirred with 1.8 g (0.013 mol) of K2CO3 in 10 ml of DMF at 80° C. for 6 hours. After cooling to room temperature, the mixture was placed in water and extracted with ether. The organic phase was washed with water, dried and filtered, and the filtrate was chromatographed on silica gel with petroleum ether/ethyl acetate 7:3 in order to separate the cis/trans isomers.
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][NH:6][C:7]=1[CH3:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:8][C:7]1[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3](=[O:12])[C:2]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=1
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1a, 12.05 g, 51.9 mmol), 3-(trifluoromethyl)phenylboronic acid (13.6 g, 71.6 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.60 g, 4.92 mmol) in acetonitrile (100 mL) is added 2 M aqueous K2CO3 solution (47 mL, 94 mmol). After stirring for 6 h at 75° C., the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in dichloromethane and extracted several times with water. The combined aqueous layer is acidified with 4 N aqueous HCl. The formed precipitate is filtered off, washed with hexanes/ethyl acetate (4:1) and dried. Yield: 13.5 g (88% of theory); ESI mass spectrum: [M+H]+=298; Retention time HPLC: 0.80 min (Z003_001).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([S:21][CH2:22][CH3:23])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: CCSc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 55 %

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 27, Step A, 2-fluoro-4-ethylthioaniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, a yellow solid was obtained which was purified by dry flash column chromatography on silica (0.5% Et2O in 1:1 CH2Cl2/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]benzoic acid as a yellow solid (55%); m.p. (Et2O) 136-139° C. 1H NMR (400 MHz, CDCl3) δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.81 (ddd, J=9.2, 6.1, 2.1 Hz, 1 H), 7.26 (dd, J=11.8, 2.0 Hz, 1 H), 7.08 (dd, J=8.3, 2.0 Hz, 1 H), 7.06 (td, J=9.7, 7.0 Hz, 1 H), 7.02 (ddd, J=9.2, 8.3, 4.7 Hz, 1 H), 2.96 (q, J=7.3 Hz, 2 H), 1.22 (t, J=7.3 Hz, 3 H). Anal. Calcd for C15H12F3NO2S: C, 55.0; H, 3.7; N, 4.3. Found: C, 55.5; H, 3.7; N, 4.3.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH:39]([C:36]1[CH:35]=[CH:34][C:33]([C@H:17]([NH:16][C:12]2[C:8]3[CH:9]=[CH:10][N:11]=[C:3]([C:2]([NH2:7])=[O:1])[C:4]=3[N:5]=[CH:6][N:14]=2)[CH2:18][NH:19][CH3:32])=[CH:38][CH:37]=1)([CH3:40])[CH3:41]
Reactant: CC(C)c1ccc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)nccc12)c1ccc(C(C)C)cc1

Procedure:
Compound 40 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. The title compound was isolated as the minor product (white solid). LC/MS [365 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.82-8.58 (m, 2H), 8.40 (s, 1H), 7.82 (s, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.52 (s, 1H), 5.89 (s, 1H), 3.68-3.54 (m, 1H), 3.51-3.43 (m, 1H), 2.98-2.78 (m, 1H), 2.65 (s, 3H), 1.17 (d, J=6.8 Hz, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: CN1CCCN(c2ccc(I)cn2)CC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CN1CCCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)CC1

Procedure:
Prepared according to general working method I from 1-(5-iodo-pyridin-2-yl)-4-methyl-[1,4]diazepan (237 mg, 0.75 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (161 mg, 0.75 mmol).
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].CCCCC.[CH3:16][Si:17]([CH2:20][Li])([CH3:19])[CH3:18].[Cl-].[NH4+]>C1COCC1>[C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C[Si](C)(C)C
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)P(C[Si](C)(C)C)C(C)(C)C
Temperature: 25 °C

Procedure:
50.00 g (0.277 mol) of Di-t-butylchlorophosphine, 304 ml of 1.0 M pentane solution of (trimethylsilylmethyl)lithium and 150 ml of THF) were refluxed under argon for 3 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of di-tert-butyl-trimethylsilanylmethyl-phosphane was 55.32 g (86%) with b.p. 50-52° C./0.5 mm. 31P NMR (C6D6)+20.05 ppm. 1H NMR (C6D6) 0.01 (s, 9H, SiMe3), 0.23 (d, 2H, 2JPH=5.34 Hz, P—CH2—SiMe3), 0.91 (s, 9H, Me3C), 0.93 (s, 9H, Me3C). Anal. Calcd. for C12H29PSi: C, 62.01; H, 12.58; P, 13.33. Found: C, 61.89; H, 12.53; P, 13.25.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11](O)=[O:12].C(Cl)(=O)C([Cl:25])=O>C1C=CC=CC=1>[CH3:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11]([Cl:25])=[O:12]
Reactant: COc1ccc(C(CC=CC=CC(=O)O)OC)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a suspension of 60% NaH (0.059 g, 1.47 mmol) washed previously with dry pentane (2×5 mL) in dry benzene (5 mL) at 5° C. was added dropwise a solution of carboxylic acid 4 (0.30 g, 1.14 mmol) in dry benzene (5 mL) via cannula. After 20 min, oxalyl chloride (117 μL, 1.34 mmol) was added via microsyringe, and then the reaction mixture was allowed to warm to rt over 30 min. After stirring for an additional 1.5 h at rt, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired acid chloride 5 in 93% yield as a red-orange oil. Without further purification, this crude product was used in the next step: 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J=15.3, 10.5 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.30 (m, 2H), 5.98 (d, J=15.3 Hz, 1H), 4.18 (dd, J=7.5, 4.8 Hz, 1H), 3.82 (s, 3H ), 3.20 (s, 3H ), 2.61 (m, 1H), 2.48 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[O:10]([C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:10]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: OC1CN2CCC1CC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(OC3CN4CCC3CC4)c2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (anhydrous, 10 mL) was treated with 3-phenoxyphenol (Aldrich, 186 mg, 1 mmol), DIAD (diisopropyl azadicarboxylate, Aldrich, 404 mg, 2 mmol), and triphenylphosphine (Aldrich, 522 mg, 2 mmol) at ambient temperature for two days. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as oil (250 mg, yield, 85%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42–1.58 (m, 1H), 1.64–1.75 (m, 1H), 1.78–1.88 (m, 1H), 2.00–2.15 (m, 1H), 2.16–2.24 (m, 1H), 2.80–3.1 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.52 (m, 2H), 6.67(dd, J=2.4, 1.0 Hz, 1H), 6 2H), 7.11 (tt, J=7.5, 1.7 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.35 (m, 2H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([C:23]#[N:24])[N:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(C(F)(F)F)=[O:27]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([C:23]([NH2:24])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C#N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carbonitrile (32 mg, 0.096 mmol) and conc. HCl (1 mL, 32.9 mmol). The reaction was stirred at room temperature for 1 h and during this time a precipitate formed. This solution was diluted with water and the precipitate was collected via filtration. Upon washing with water the precipitate dissolved. The layers were separated and the aqueous was extracted with ether (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. This crude mixture was taken up in DCE (1 mL) and TFA (1 mL, 12.98 mmol). The vial was sealed and the reaction heated to 80° C. for 1 h before cooling to room temperature and stirring for an additional 2 h. The solution was concentrated and the crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (16.2 mg, 0.046 mmol) as a white solid. LC/MS m/z 352 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.07-7.86 (m, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.71 (t, J=7.2 Hz, 1H), 7.52-7.47 (m, 2H), 7.46-7.36 (m, 4H), 4.73-4.42 (m, 1H), 2.50 (s, 3H)