Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[Li+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C.O>[CH:18]([OH:20])=[O:19].[CH3:30][C@H:5]1[CH2:6][C@@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:65]4[CH2:70][CH2:69][O:68][CH2:67][CH2:66]4)=[O:20])=[CH:16][CH:15]=3)[CH:9]=2)[N:4]1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Product: O=CO
Reaction time: 2 h
Yield: 10 %

Procedure:
Crude lithium 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 58) (40 mg) and HATU (41 mg, 0.108 mmol) in DMF (0.5 mL) were treated with DIPEA (51.2 μL, 0.294 mmol) and the mixture shaken and sonicated until a solution was formed (<2 min). This solution was added to morpholine (17 μL, 0.194 mmol), the mixture briefly shaken then left to stand at room temperature for 2 h. A further portion of morpholine (34 μL, 0.388 mmol) was added and the mixture left to stand overnight. The mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by MDAP (formate) to give 1-((2S,4R)-2-methyl-6-(4-(morpholine-4-carbonyl)phenyl)-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone formate (20 mg, 0.039 mmol, 10% yield) as a pale pink glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16]O)=[CH:4][C:3]=1[CH3:18].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:16][C:9]1[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:18])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(CO)c(-c2ccc(F)c(C)c2)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Reaction time: 1 h

Procedure:
4'-Fluoro-2-hydroxymethyl-3,3',5-trimethyl-1,1'-biphenyl (2.77 g, 11.3 mmoles) was added in divided portions to thionyl chloride (10 ml) and then heated with stirring in an 80° bath for one hour. The reaction was then diluted with 50 ml of dry toluene and the solvent was evaporated in vacuo to leave 3.27 g of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=481.0 (M+H)+
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.[Na+]>[Cl-].[Na+].O.C(O)(=O)C>[CH3:1][S:2][CH2:4][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CS(C)=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
Dimethylsulfoxide (9.25 g, 118 mmol) and acetic anhydride (15.6 g, 153 mmol) were heated to 80° C. for 24 hours. The reaction solution was cooled to room temperature, then glacial acetic acid (90 ml), sodium acetate (9.7 g, 118 mmol) and sodium p-toluenesulfinate (31.6 g, 178 mmol, dried in vacuo overnight with P2O5 at 50° C.) were added. The mixture was heated to 100° C. for 24 hours. Brine (150 ml) was added and the solution was extracted with methylene chloride (5X, 100 ml). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a gummy solid. The solid was recrystallized from 95% ethanol (3B) to yield 8.68 g of white crystals of (methylthio)(p-toluenesulfonyl)methane: m.p. 81°-83° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCCSc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
6-[(2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)amino]nicotinonitrile (Example 88) is prepared in analogy to Example 82 from Example 47A (200 mg, 0.4 mmol), 2-chloro-5-cyanopyridine (75 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.8 ml, 4 mmol). 92 mg (47% of theory) of product are obtained as solid after purification by preparative RP-HPLC (gradient of eluent: water:acetonitrile 90:10 to 10:90).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=CC=2N=N1.[C:28]12(NC)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[CH3:40][C:41]1[C:45]([C:46]([OH:48])=O)=[CH:44][NH:43][N:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:28]12([CH2:12][NH:8][C:46]([C:45]3[C:41]([CH3:40])=[N:42][NH:43][CH:44]=3)=[O:48])[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: Cc1n[nH]cc1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNC12CC3CC(CC(C3)C1)C2
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
BOP (3.53 g, 8 mmol) is added to a solution of adamantan-1-yl-methylamine (1.32 g, 8 mmol), 3-methyl-1H-pyrazole-4-carboxylic acid (1 g, 7 mmol) and DIEA (2.6 g, 20 mmol) in DCM (25 mL). The solution is stirred overnight and evaporated, and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried and evaporated. The residue is triturated with DCM and air-dried to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.009 g of product in 39% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[N:14][CH:13]=C(Cl)[C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:17][NH:18][NH2:19].[CH2:20](O)CCC>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[N:14][CH:13]=[C:17]3[N:18]([CH3:20])[N:19]=[C:10]([NH2:11])[C:9]=23)=[CH:6][CH:7]=1
Reactant: CNN
Reactant: N#Cc1c(Cl)cncc1-c1ccc(N)cc1
Reactant: CCCCO
Product: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Temperature: 25 °C

Procedure:
The product from Example 1C (150 mg, 0.65 mmol) and methylhydrazine (0.35 mL) in n-butanol (2 mL) was heated in a sealed vial at 190° C. for 30 minutes with stirring in a Smith Synthesizer microwave oven (at 300W). The reaction mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic extract was dried (Na2SO4), filtered, and the filtrate was concentrated to provide 0.08 g of the title compound. MS (ESI(+)) m/e 240 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH2:25][CH2:23][OH:24])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCCO)cn1
Yield: 60 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (500 mg, 1.4 mmol) was converted, using ethanolamine instead of rac-2-amino-1-propanol, to the title compound (280 mg, 60%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=334.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14]Br>CN(C)C=O>[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:14][CH2:13]1
Reactant: BrCCBr
Reactant: N#CCc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cnccn2)CC1
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a suspension of sodium hydride (0.386 g, 16.1 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added dropwise a solution of 2-(pyrazin-2-yl)acetonitrile (0.55 g, 4.6 mmol) and 1,2-dibromoethane (2.25 g, 11.9 mmol) in anhydrous N,N-dimethylformamide (8 mL) over a period of 10 min at room temperature. The mixture was stirred for 18 h, then was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 100% dichloromethane) to afford 1-(pyrazin-2-yl)cyclopropanecarbonitrile (210 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[N:6]=[C:5]2[SH:28].[CH2:29](N(CC)CC)C.CI.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[N:6]=[C:5]2[S:28][CH3:29]
Reactant: CCOP(=O)(OCC)SCc1ccc(-c2nc(S)c3cc(Br)ccc3n2)cc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)SCc1ccc(-c2nc(SC)c3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.60 g quantity of the compound obtained in Example 52 was dissolved in 10 ml of THF, and 0.2 ml of triethylamine and 0.1 ml of methyl iodide were serially added thereto with stirring at room temperature. The stirring was continued at room temperature for 30 minutes. After adding 30 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform: n-hexane=2:1) and recrystallized from diethyl ether-n-hexane to provide 0.43 g of the objective compound as yellow crystals (melting point: 126°-127° C.).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-])=O)=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2.[H][H]>C(OC(=O)C)(=O)C.C(O)(=O)C.[Pd]>[OH2:1].[C:2]([NH:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[CH:9]=2)[C:4]([CH3:19])=[N:3][C:2]=1[OH:1])(=[O:1])[CH3:11].[C:8]([NH:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[CH:9]=2)[C:4]([CH3:19])=[N:3][C:2]=1[OH:1])(=[O:15])[CH3:7]
Reactant: [H][H]
Reactant: COc1cc2c(C)nc(O)c([N+](=O)[O-])c2cc1OC
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(C)nc(O)c(NC(C)=O)c2cc1OC
Product: O
Yield: 64 %

Procedure:
A slurry of 2.028 grams 3-hydroxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (BA) (7.67 mmol) in 28 ml acetic anhydride and 180 ml acetic acid was hydrogenated using 0.8 grams of a 10% palladium on carbon catalyst at 25 psi hydrogen pressure in a Parr hydrogenator for 3 hours. The mixture was filtered through a Celite pad, and the collected solids were washed with acetic acid. The filtrate and the wash liquids were combined and evaporated to dryness. The residue was recrystallized from methanol to provide 0.70 grams of Compound BG (33% yield) having a melting point of >300° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:25][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:25])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-chloro-8-(2-fluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (40 mg, 0.1 mmol) in tetrahydrofuran (0.2 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.50 mL, 0.70 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step (32 mg, 92%). LCMS calculated for C17H12ClFNO(M+H)’ : m/z=300.1; found: 284.0.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[C:11]1[C:23]([OH:25])=O>>[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[C:11]1[C:23]([Cl:1])=[O:25]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reactant: CC(C)=C(Cl)N(C)C
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Cl
Reaction time: 8 h

Procedure:
N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (31 μL, 0.23 mmol) was added to a mixture of 1-methyl-4-(BOC amino)pyrrole-2-carboxylic acid (50 mg, 0.21 mmol) in CDCl3 (200 mL). After a few minutes, the 1H-NMR of the reaction mixture showed complete conversion of the acid to the acid chloride. The proton spectrum of this solution of acid chloride did not change on standing overnight at room temperature. 1H NMR (CDCl3): δ 7.35 (br s, 1H), 6.93 (d, J=2 Hz, 1H), 6.46 (br s, 1H), 3.82 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>C(O)C>[CH3:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[N:1]=[C:19]=[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][NH:13]1
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Reactant: O=Cc1ccccn1
Solvent: CCO
Product: Cc1ccc(N=C=C2C=CC=CN2)c(C)c1[N+](=O)[O-]

Procedure:
3.3 g of 4-amino-2-nitro-m-xylene and 2.1 g of 2-pyridinealdehyde were dissolved in 50 ml ethanol and left to stand. Crystals slowly precipitated and were filtered off under suction and washed with ethanol. The dried product (3.0 g) had a melting point of 114° to 116° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]#[N:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.[CH:27]([N-]C(C)C)([CH3:29])[CH3:28].[Li+].C(Br)C#C.O>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][C:9]([CH2:29][C:27]#[CH:28])([C:14]#[N:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C#N)C3)c1C
Reactant: CC(C)[N-]C(C)C
Agent: C#CCBr
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCC1(C#N)Cc2nn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(c23)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
4-Amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carbonitrile of Example 4 (50 mg) was dissolved in tetrahydrofuran (5 ml). A 2 N solution of lithium diisopropylamide in tetrahydrofuran (0.050 ml) was added at −78° C., and the mixture was stirred at the same temperature for 15 minutes. Then, propargyl bromide (0.015 ml) was added and the mixture was stirred at the same temperature for three hours. Water was added to the reaction solution, and then the mixture was heated to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by reversed phase liquid chromatography. The resulting solid was dissolved in a 50% solution of trifluoroacetic acid in dichloromethane (1 ml), followed by stirring for one hour. The reaction solution was concentrated under reduced pressure and azeotropically distilled with ethanol. The resulting solid was washed with ether to obtain the title compound (2 mg, 99%) as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([Mg]Br)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:2].BrC1C=CC(C2C=CC=CC=2)=C(C=C)C=1.[Mg].[O:33]=[C:34]1[CH2:38][N:37]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[C@H:36]([C:48]([O:50][CH3:51])=[O:49])[CH2:35]1>C1COCC1.C1(C)C=CC=CC=1>[OH:33][C@:34]1([C:7]2[CH:6]=[CH:5][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([CH:1]=[CH2:2])[CH:8]=2)[CH2:38][N:37]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:47])[CH3:45])=[O:40])[C@H:36]([C:48]([O:50][CH3:51])=[O:49])[CH2:35]1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1cc([Mg]Br)ccc1-c1ccccc1
Agent: C=Cc1cc(Br)ccc1-c1ccccc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 18.2 %

Procedure:
(2-vinylbiphenyl-4-yl)magnesium bromide (2.66 g, 9.38 mmol) solution, made by refluxing Intermediate 7 with 1 eq. of magnesium turnings in THF, was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (2.7 g, 9.38 mmol) in toluene (75 mL) at 0° C. and stirred for 1 hr and then quenched with sat. NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (800 mg, 1.711 mmol, 18% yield). LCMS: rt=1.85 min. [M+Na]+=490; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(Oc3ccccc3)cccc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1O
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (103 mg, 0.35 mmol), N-bromosuccinimide (65 mg, 0.37 mmol), benzoyl peroxide (4.2 mg, 0.02 mmol), and carbon tetrachloride (2.5 mL) was refluxed for 4 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (128 mg): MS: (+) m/z 374.0, 376.0 (M+1, 79Br/81Br), MS: (−) m/z 372.1, 374.1 (M−1, 79Br/81Br).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:11]([CH2:17]CO)[C:12]([O:14][CH2:15]C)=[O:13])[CH:7]=[CH:8][CH:9]=1>O.C(O)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:3][C:4]1[CH:5]=[C:6](/[C:10](=[C:11]2\[C:12](=[O:13])[O:14][CH2:15][CH2:17]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(F)c2)cc1
Yield: 15.5 %

Procedure:
3.3 g of sodium hydroxide dissolved in 10 ml of water are added to a solution of 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)-2-propenoate, prepared in Example 12, in 50 ml of ethanol and the mixture is refluxed for 2 hours. After evaporation to dryness, the residue is taken up with water, acidified with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give an oily residue. The oil is solubilized in 150 ml of toluene, and 10 mg of paratoluenesulphonic acid are added. The mixture is refluxed and the water formed is removed with a Dean-Stark apparatus. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulphate and evaporated under vacuum and the residue is chromatographed on silica in t-butyl methyl ether to give 4 g of (Z)-3-[1-(3-fluorophenyl)-1-(4-methanesulphonylphenyl)methylidene]dihydrofuran-2-one (2nd product eluted) in the form of crystals melting at 153-154° C.