Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][C:13]1([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Fc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2cccc(F)c2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
925 mg magnesium were stirred into 19 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 4.95 g 3-fluorobenzyl chloride in 19 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 29 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(3-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (5.75 g of yellow solid) was stirred, without further purification, with a mixture of 14 ml conc. hydrochloric acid (32 per cent by weight) and 8 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 30 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 40 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 4.71 g 4-dimethylamino-4-(3-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: [S:1](Cl)([OH:4])(=O)=[O:2].[CH3:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1.[NH3:17]>>[CH3:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[S:1]([NH2:17])(=[O:4])=[O:2]
Reactant: COc1ccc(C)cc1OC
Reactant: N
Reactant: O=S(=O)(O)Cl
Product: COc1cc(C)c(S(N)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18 gm (0.07 mol) of the compound obtained in step (a) were suspended in 200 ml of concentrated ammonia, and the suspension was stirred at room temperature for 4 hours. Thereafter, the mixture was suction-filtered, the filter cake was washed with water, and the desired sulfonamide was obtained as an amorphous product after drying. Rf -value (benzene/acetone = 1/1): 0.6.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OC(C)(C)C)=O)[C@H:10]1[CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=O)[CH2:2][CH2:3][CH3:4].[C:33]([CH2:36][CH2:37][CH:38]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH2:39]1)(=[O:35])[NH2:34]>>[CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:23][C:24]([CH3:29])([CH3:30])[CH2:25][C:26]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:47][CH:38]([CH2:37][CH2:36][C:33](=[O:35])[NH2:34])[CH2:39]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Reactant: NC(=O)CCC1CNc2ccccc2C1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(CCC(N)=O)Cc2ccccc21

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 205 mg of 3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinoline, the title compound is obtained via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (X)=0.08; Rf (V)=0.56; Rt (VI)=30.8 min) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-(2-carbamoyl)ethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (P)=0.32; Rt (VI)=26.8 min; FAB-MS: (M+H)+ =603) in a manner analogous to Example 1) as a diastereomer mixture: Rf (V)=0.21; Rt (VI)=20.3 min; FAB-MS: (M+H)+ =503.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.O1CCCC1.C1(C)C=CC=CC=1>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Nc1nccnc1S2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
259 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate was dissolved in a solvent mixture of 3 l of methylene chloride with 0.5 l of tetrahydrofuran under a nitrogen atmosphere. Next, 2.5 l of a 1.01 M solution of diisobutylaluminum hydride in toluene was added dropwise thereinto while cooling the mixture so as to maintain the temperature in the system at 15° C. or below. After the completion of the reaction, the reaction mixture was poured into a mixture of 5 kg of ice with 3 l of methylene chloride. After adding 5 l of tetrahydrofuran, the resulting mixture was stirred for 1 hour. Then it was filtered and the filtrate was washed with water. After distilling off the solvent under reduced pressure, the obtained crystals were washed with diisopropyl ether to thereby give 125 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.41 g, 0.7 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added 1N sodium hydroxide (2 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.34 g, 91.9%) as crystals.
Reaction SMILES: ClC(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8](O)[CH:9]=[C:10]([Cl:12])[CH:11]=1.[C:14](=[O:17])([O-])[O-].[Cs+].[Cs+].O.[NH2:21][NH2:22]>CC(C)=O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:17][C:14]1[C:8]([CH2:9][CH3:10])=[N:21][NH:22][C:11]=1[CH2:6][CH3:7]
Reactant: NN
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 125.2 %

Procedure:
A mixture of the chloroketone of Preparation 2 (5 g, 30.8 mmol), 3,5-dichlorophenol (5 g, 30.8 mmol), caesium carbonate (10 g, 30.8 mmol) and acetone (40 ml) was heated under reflux for 18 hours. After cooling, a solid was removed by filtration and washed with dichloromethane (100 ml). The combined filtrates were concentrated under reduced pressure. The crude product was dissolved in ethanol (20 ml), hydrazine hydrate (1.5 ml, 30.8 mmol) was added and the mixture was heated at 60° C. for 30 minutes under nitrogen. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ether:pentane (1:1, by volume) to provide the title compound (5.5 g) as a yellow oil which solidified on standing to leave a yellow solid, m.p. 114-115° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:11]=[N:12][C:13]([Br:16])=[CH:14][CH:15]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[N:12]=[CH:11][C:10]([CH:8]2[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 70318 %

Procedure:
5-(6-bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (650.0 mg, 1.7 mmol) prepared in Step 2 and a solution of potassium hydroxide (185.0 mg, 3.3 mmol) in distilled water (10.0 mL) were added to methanol (10.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 455.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: [Cl:1][S:2]([CH2:5][C:6](Cl)=[O:7])(=[O:4])=[O:3].[CH3:9][OH:10]>CCOCC>[CH3:9][O:10][C:6](=[O:7])[CH2:5][S:2]([Cl:1])(=[O:4])=[O:3]
Reactant: CO
Reactant: O=C(Cl)CS(=O)(=O)Cl
Solvent: CCOCC
Product: COC(=O)CS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of chlorosulfonylacetyl chloride (419 μL, 3.955 mmol, 1 eq.) in Et2O (4 mL), at 0° C. was added MeOH (160 μL, 3.955 mmol, 1 eq.). The reaction mixture is stirred at 0° C. for 3 h, then concentrated in vacuo to give chlorosulfonyl-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([O:30]C)=[O:29])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=[O:29])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
In methanol (40 ml) and THF (60 ml) was dissolved methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was-added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight. To the mixture was added 1N sodium hydroxide solution (2.5 ml), and the mixture was stirred at room temperature overnight and concentrated. The residue was neutralized with 1N hydrochloric acid, precipitated crystals were filtered and washed with water to give 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=[O:6].Br[C:17]1C=C(C=C(O)C=1)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Product: COC(=O)c1cc(Br)cc(OC(F)(F)F)c1

Procedure:
Prepared from 3-bromo-5-(trifluoromethoxy)benzoic acid according to the procedure for methyl 3-bromo-5-hydroxybenzoate. LCMS-ESI (m/z) calculated for C9H6BrF3O3: 299.0; no m/z observed, tR=4.08 min. 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J=3.9, 2.4 Hz, 1H), 7.83 (dt, J=2.2, 1.2 Hz, 1H), 7.57 (ddd, J=2.4, 1.8, 0.9 Hz, 1H), 3.99-3.87 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: O=C=Nc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4 g (18.4 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 24 hours with 3.6 g (18.4 mmol) of p-bromophenylisocyanate and 1.86 g (18.4 mmol) of triethylamine in 40 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 150 ml of 2-N hydrochloric acid and 100 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is taken up in 500 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 250 ml portions of semi-saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 300 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil is covered with 5 ml of ethanol, the product separating out after standing for several days. The crystals are filtered off under suction, digested with a small amount of ethanol and dried. There is obtained 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 138°-140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][N:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16][CH2:15]1)([O-])=O.[H][H].C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(O)C.[C].[Pd].CO>[C:45]([NH:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][N:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16][CH2:15]1)(=[O:47])[CH3:46]
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3ccc([N+](=O)[O-])cc23)CC1
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2ncnc(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 464.1 mg (0.99 mmol) of Compound 311 in 15 ml of ethanol was added 100 mg of 10% palladium-carbon, followed by stirring in a stream of hydrogen at room temperature for 4 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. The residue was dissolved in 15 ml of dichloromethane, and 0.70 ml (5.02 mmol) of triethylamine and 0.19 ml of acetic anhydride were added thereto, followed by overnight stirring at room temperature. After methanol was added to the reaction mixture, the solvent was evaporated, and the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(C)C>[ClH:1].[C:15]([C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:14][CH2:13][O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1)#[CH:16]
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OCO4)c1
Product: Cl

Procedure:
4-Chloro-6,7-methylenedioxyquinazoline (200 mg, 1.04 mmol) and 3-ethynylaniline (127 mg, 1.09 mmol) were refluxed in 5 mL of isopropyl alcohol for 16 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 266 mg (79%); mp >350° C.
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4])#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:4][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([C:1]1[NH:27][N:26]=[N:25][N:2]=1)[CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C#N)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21)c1nnn[nH]1
Temperature: 110 °C
Yield: 29.3 %

Procedure:
A mixture of (1aR,5aR)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (cyano-dimethyl-methyl)-amide (100 mg, 0.293 mmol), sodium azide (28.5 mg, 0.439 mmol) and triethylamine hydrochloride (81 mg, 0.585 mmol) in DMF (2 mL) was heated in a heavy-walled sealed tube under microwave irradiation at 110° C. for 1 h. Another 50 mg sodium azide and 150 mg triethylamine hydrochloride were added, and the mixture was heated under microwave for another 5 h at 125° C. The mixture was purified by prep HPLC to give the title compound as a white solid (33 mg). LCMS m/z=385.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35 (td, J=4.4, 3.4 Hz, 1H), 1.23 (td, J=7.8, 4.6 Hz, 1H), 1.757 (s, 3H), 1.764 (s, 3H), 2.21-2.28 (m, 1H), 2.66 (d, J=16.6 Hz, 1H), 2.71-2.75 (m, 1H), 2.79 (dd, J=16.6, 6.4 Hz, 1H), 7.54 (dd, J=5.4, 1.9 Hz, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.42 (bs, 1H), 8.51 (d, J=5.4 Hz, 1H), 16.0 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)=[C:9]([F:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Mg]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:27]2[CH2:29][CH2:28]2)[C:9]([F:26])=[CH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: FC(=CCc1ccc(F)c(Oc2ccccc2)c1)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 1-(p-chlorophenyl)-1-cyclopropyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene (26 g, 0.064 mol) in a methanol/tetrahydrofuran solution (15:1) is treated with magnesium turnings (7.72 g, 0.317 mol), stirred at room temperature for 4 hours, quenched with hydrochloric acid, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2 N hdyrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (5:95) gives the title product as an oil (21.4 g, 82%) which is identified by NMR spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:19]2)=[CH:14][CH:13]=1.[C:35](O)([C:37]([F:40])([F:39])[F:38])=[O:36].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[F:38][C:37]([F:40])([F:39])[C:35]([N:25]1[CH2:26][CH2:27][N:22]([CH:18]2[CH2:19][C:20]3[CH:21]=[C:12]([N:3]4[C:4](=[O:11])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:2]4=[O:1])[CH:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)[CH2:23][CH2:24]1)=[O:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3ccc(N4C(=O)c5ccccc5C4=O)cc3C2)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1ccc2c(c1)CC(N1CCN(C(=O)C(F)(F)F)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with tert-butyl 4-[7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate (300 mg, 0.65 mmol) and a stir bar was added TFA (2 mL). The mixture was allowed to stir at RT for 1 hour. LC showed complete removal of the Boc group. TFA was removed under reduced pressure, and the residue was dissolved in DCM (5 mL). To the solution was added pyridine and trifluoroacetic anhydride (0.27 mL, 2.0 mmol). LC showed formation of the desired product within 30 minutes. The product was purified by MPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=O)[CH2:23]2)=[CH:18][CH:17]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)Nc5ccccc5)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 3, 120 mg, 0.29 mmol), aniline (55 mg, 0.59 mmol), HOBt (58 mg, 0.43 mmol) in 6 mL of DMF was added EDC (82 mg, 0.43 mmol) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc, and the resulting solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel column chromatography (30% to 100% EtOAc/hexane then to 5% MeOH/EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 484.5 (M+H). Calc'd Exact Mass for C28H25N3O5: 483.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (470 mg, 1.50 mmol) was reacted with 4-((dimethylamino)methyl)aniline (451 mg, 3 mmol) to afford the desired product (402 mg, 63%) as a yellow solid. ESI MS m/z 426 [C22H24BrN3O+H]+