Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=[O:26])[O:19][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:23]
Reactant: CCN(CC)C(=O)Cl
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)OCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
0.1 g (0.403 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were solubilised in 3 ml of dimethylformamide with magnetic stirring. The mixture was cooled to 0° C., 0.048 g (1.208 mmol) of sodium hydride (60% by mass) were added portion wise. The mixture was stirred for 10 min at 0° C. and then 0.204 ml (1.611 mmol) of diethylcarbamoyl chloride were added. The cold bath was withdrawn, the mixture was stirred at r.t. for 2 h before being treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 3×10 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, 6/4, v/v). 0.101 g (yield=72%) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methyl diethylcarbamate were obtained as a pale yellow solid. LC-MS: m/z=348 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.61 (d, J=6.8 Hz, 1H), 7.74-7.59 (m, 3H), 7.53-7.38 (m, 4H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 5.30 (s, 2H), 3.22 (q, J=7.1 Hz, 4H), 1.01 (t, J=7.1 Hz, 6H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([O:14][CH3:15])[CH:8]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:14][CH3:15])[CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of sodium bicarbonate (3.12 g, 0.0371 mol) in water (35 mL) was added to a solution of 4-bromo-2-methoxyaniline (3.00 g, 0.0148 mol) in dioxane (50 mL). The resulting mixture was stirred for 5 minutes and benzyl chloroformate (3.8 g, 0.022 mol) was added dropwise over 3 minutes. The reaction mixture was for two hours, then dioxane was removed under reduced pressure and the water phase was extracted twice with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate and after filtration concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield benzyl N-(4-bromo-2-methoxyphenyl)carbamate (3.75 g, 0.011 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) 8.72 (s, 1H), 7.61 (d, 1H), 7.38 (m, 5H), 7.20 (s, 1H), 7.10 (d, 1H), 5.14 (s, 2H), 3.81 (s, 3H). TLC (ethyl acetate/heptane 1:9) Rf 0.21.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[S:20][C:19]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:18][CH:17]=1.Cl>O1CCCC1>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[C:19]1[S:20][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:18]=1)#[N:24]
Reactant: N#Cc1ccccc1-c1ccc(CBr)s1
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.71 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (3.65 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 2-[5-(bromomethyl)thiophen-2-yl]benzonitrile (3.20 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (3.30 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C)cc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99 %

Procedure:
A solution of 5.5 g (27.9 mmole) of N-(3,5-dimethylphenyl)aniline, 27.9 mL of 1.93M phosgene in toluene and 15 mL of toluene was heated at 90° C. under nitrogen for 2 hours with stirring. The solution was cooled, flushed with nitrogen for 2 hours to remove excess phosgene and concentrated in vacuo to give 7.15 g (99%) of a red oil.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:18]#[C:19][Si](C)(C)C)=[C:16]([CH2:24][CH3:25])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:18]#[CH:19])=[C:16]([CH2:24][CH3:25])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1c(CC)ncnc1N[C@H]1CC[C@@H](C(C)(C)C)CC1

Procedure:
2.8 g (7.7 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-(trimethylsilylethynyl)pyrimidine (Example 7) were stirred in 25 ml of a 0.4 molar solution of potassium hydroxide in methanol at room temperature for 4 hours. The mixture was concentrated, the residue was taken up in toluene/water and the organic phase was dried and concentrated to leave 1.85 g (84.2% of theory) of a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1)[CH3:2].FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[K+]>O>[N+:24]([C:11]1[C:12]([CH2:13][CH3:14])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cc2c(cc1CC)=NC(=O)C(=O)N=2
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1CC
Yield: 69.1 %

Procedure:
6,7-Diethyl-2,3-quinoxalinedione 25 (218 mg, 1.0 mmol) was added to trifluoroacetic acid (8 mL; Sigma). To this suspension was added potassium nitrate (121.2 mg, 1.2 mmol; Baker) in one portion with stirring under N2. The reaction was stirred at room temperature for 48 h. Trifluoroacetic acid was evaporated in vacuo to give a residue. Water (10 mL) was added to this residue with vigorous stirring. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo to give 182 mg (69%) of the title compound 26 as a yellow solid; mp 270-272° C. (dec.); 1H NMR (DMSO-d6,300 MHz) δ 1.137 (m, 6H), 2.622 (m, 4H), 7.088 (s, 1H), 11.762 (s, 1H), 12.028 (s, 1H). EIMS m/e 263 (100, M+). (HPLC purity 100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:13][C@H:14]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]1)(=O)C1C=CC=CC=1.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[N+:1]([C:21]1[CH:22]=[CH:23][C:18]([C@H:16]2[CH2:15][C@H:14]([OH:13])[CH2:17]2)=[CH:19][CH:20]=1)([O-:4])=[O:2]
Reactant: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc([C@H]2C[C@H](O)C2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a mixture of nitric acid (fuming, 2.3 mL) and acetic anhydride (25 mL) was added dropwise a mixture of trans-3-phenylcyclobutyl benzoate (step 2, 3.7 g, 24.6 mmol) and sulfuric acid in acetic anhydride (25 mL) at −23° C. The resulting mixture was stirred in an ice-bath for 1.5 h. The mixture was poured into ice water (200 mL) and extracted with dichloromethane (2×100 mL). The organic layer was washed with water and brine (100 mL), then dried (Na2SO4), and concentrated. The oily residue was dissolved in methanol (100 mL), and 4N aqueous LiOH (50 mL) was added. The resulting mixture was stirred at room temperature for 10 min, then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 2.7 g (56%) of the title compound as a pale yellow oil: MS (EI) m/z 193 (M+); 1H-NMR (CDCl3) δ 8.18 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 4.62–4.52 (1H, m), 3.81–3.71 (1H, m), 2.54–2.45 (4H, m).
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1Br.[CH2:50]([O:52][C:53]([Sn](CCCC)(CCCC)CCCC)=[CH2:54])[CH3:51]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1[C:50]([O:52][CH2:53][CH3:54])=[CH2:51]
Reactant: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(-c2ccc(C(=O)OC)cc2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
Compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (40 mg, 0.053 mmol) under Argon, was mixed with Pd(PPh3)4 (12 mg, 0.01 mmol, (1-ethoxyvinyl)tributylstannane (85 uL, 0.25 mmol) and dioxane (3 mL). The resulting mixture was heated at 100° C. and stirred over night. After cooled to room temperature, the mixture was filtered through 10% KF on silica gel and washed with EtOAc. After concentration, the crude product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate was used in the next step directly without further purification. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C41H53N5O5Si2 751.4, observed LCMS m/z 752.3 (M+H).
Reaction SMILES: CC1C2COC(=O)C=2C=CC=1[C@@H:12]1[CH2:14][O:13]1.Br[C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[C:26]([F:29])([F:28])[F:27]>>[O:13]1[CH2:14][CH:12]1[C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[C:26]([F:29])([F:28])[F:27]
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: O=C1OCc2c1ccc(Br)c2C(F)(F)F
Product: O=C1OCc2c1ccc(C1CO1)c2C(F)(F)F

Procedure:
5-(Oxiran-2-yl)-4-(trifluoromethyl)-2-benzofuran-1 (3H)-one was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (INTERMEDIATE 2) starting from 5-bromo-4-(trifluoromethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]1[S:12](=[O:14])(=[O:13])[O:11][CH2:10][CH2:9]1>>[CH2:1]([NH:7][CH2:10][CH2:9][CH2:8][S:12]([OH:14])(=[O:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: O=S1(=O)CCCO1
Product: CCCCCCNCCCS(=O)(=O)O

Procedure:
In the manner of previous Examples n-hexylamine was reacted with propanesultone to yield the 3-hexylamino propylsulfonic acid, mp
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])[CH:8]=[CH:9][C:2]=12.[F:17][CH2:18][CH2:19][NH2:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][CH2:18][CH2:19][NH:20][C:14]([CH2:13][NH:12][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[C:3]([CH:6]=1)=[N:4][O:5][N:1]=2)=[O:11])=[O:16]
Reactant: O=C(O)CNC(=O)c1ccc2nonc2c1
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1ccc2nonc2c1)NCCF
Temperature: 5 °C

Procedure:
221 mg (1 mmol) [(benzo[1,2,5]oxadiazole-5-carbonyl)-amino]-acetic acid, 120 mg (1.2 eq.) 2-fluoroethylamine, 162 mg (1.2 eq.) HOBt and 230 mg (1.2 eq.) EDC.HCl are dissolved in 18 mL DMF and cooled to 5° C. 0.7 mL (4 eq.) Hünig's base are added under stirring, the reaction mixture is stirred for an additional 3 hours at room temperature then extracted with water and ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulfate and evaporated to yield the desired product as a beige solid. MS (ES+): 267 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1.[Cl:32][C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:41]=1[CH3:50].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[C:37]([NH:39][CH2:2][C:3]2[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=2)[CH:36]=[CH:35][C:34]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][C:41]=1[CH3:50]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CBr)cn1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3C)c(Cl)c2)cn1
Temperature: 100 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (27 mg, 0.05 mmol), 2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (20 mg, 0.07 mmol) and iPr2NEt (27 μL, 0.16 mmol) were dissolved in toluene (3 mL) and the resulting mixture was heated at 100° C. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].C(OC(=O)C1C=CN=[C:22]([CH:26]2[CH2:28][CH2:27]2)C=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[C:22]([CH:26]3[CH2:28][CH2:27]3)[N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccnc(C2CC2)c1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2c(C3CC3)nccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloro-2-cyclopropylisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (7/3) gives the desired product as colorless oil;
Reaction SMILES: [SH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7](=[O:10])[CH2:8][NH2:9])=[O:5].Cl[C:16]([O:18][CH2:19][CH2:20][Br:21])=[O:17]>CN(C)C(=O)C>[Br:21][CH2:20][CH2:19][O:18][C:16]([S:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7](=[O:10])[CH2:8][NH2:9])=[O:5])=[O:17]
Reactant: NCC(=O)NC(=O)c1ccccc1S
Reactant: O=C(Cl)OCCBr
Solvent: CC(=O)N(C)C
Product: NCC(=O)NC(=O)c1ccccc1SC(=O)OCCBr
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of N-(2-mercaptobenzoyl)glycinamide (1.05 g, 5.0 mmol) in N,N-dimethylacetamide (DMA, 25 ml) was added 2-bromoethyl chloroformate (1.22 g, 6.5 mmol). The reaction mixture was stirred for 8 h, the solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml. The resulting precipitate was filtered, washed with water and dried over CaCO2, Yield: 89%. 1H NMR (DMSO-d6): 3.71 (t, 1H, CH2), 3.78 (d, 2H, CH2), 3.86 (t, 1H, CH2), 4.45 (t, 1H, CH2), 4.51 (t, 1H, CH2), 7.11 (brs, 1H, NH2), 7.30 (brs, 1H, NH2), 7.36-7.58 (m, 5H, Ar—H, NH2), 8.26 (t, 2H, Py-H), 8.36 (t, 1H, NH), 8.52 (t, 1H, NH), 8.66 (t, 1H, Py-H), 9.12 (d, 21, Py-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:16]=[N:15][N:14]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc3nncn3c2)cc1

Procedure:
A mixture of 8.5 g. of 5-(4-chlorophenyl)-2-hydrazinopyridine and 80.0 ml. of ethyl orthoformate is refluxed for 5 hours. The mixture is filtered and the solid is washed with hexane to give 6.5 g. of the product of the Example, m.p. 259°-262° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(Cl)OCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chloromethyl chloroformate (2.84 g) in dichloromethane (10 ml) was added dropwise with stirring to an ice-cold solution of 3-(N-tert-butoxycarbonylamino)-propylamine (3.49 g) and diisopropylethylamine (3.10 g) in dichloromethane (30 ml). After stirring for a further 3 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.I[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[N:14]([CH3:26])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1N(C)C(C)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-3-phenyl-propyl)-amine and iodomethane.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([OH:21])(=O)[C:17]#[C:18][CH3:19].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1>O1CCCC1>[F:44][C:42]([F:43])([F:45])[C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:16](=[O:21])[C:17]#[C:18][CH3:19])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
Isobutyl chloroformate (1.56 g, 11.4 mmol) and N-methylmorpholine (1.15 g, 11.4 mmol) were added to an ice cold solution of 0.961 g (11.4 mmol) of 2-butynoic acid in 40 mL of tetrahydrofuran under N2. After stirring for 10 min, a solution of 1.50 g (4.57 mmol) of 6-amino-4-[(3-trifluoromethylphenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran was added dropwise. After stirring at 25° C. overnight, volatile material was removed and the residue was slurried in water and filtered. The crude product was washed 3 times with small portions of hot ethyl acetate and then dried in vacuo (45° C.) to give 0.831 g of yellow solid: mass spectrum (electrospray, m/e): M+H 395.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]=[C:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1
Reactant: COc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 5-methoxy-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline (189 mg, 619 μmol, from step 2), MeOH (3 mL), sodium borohydride (21.8 μL, 619 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline. MS (ESI pos. ion) m/z: 308 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc(OC)c1
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added and, the ethyl acetate phase was washed with 2N-hydrochloric acid 50 ml twice and with saturated sodium bicarbonate solution 50 ml. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 388.5 mg.