Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([O:14][CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].[C-]#N.[K+].C1N2CC[N:29](CC2)[CH2:28]1.O>CS(C)=O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([O:14][CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10]([C:28]#[N:29])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C1CN2CCN1CC2
Reactant: C=CCOC(=O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOC(=O)c1cnc(C#N)nc1OCC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester (0.62 mmol) in DMSO (1.0 mL) are added KCN (0.94 mmol), DABCO (0.19 mmol), and H2O (0.10 mL) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the titled compound; 1H NMR (CDCl3) δ 0.19-0.20 (m, 2H), 0.21-0.33 (m, 2H), 0.91-0.96 (m, 2H), 1.23-1.33 (m, 3H), 1.72-1.85 (m, 4H), 4.38 (d, 2H), 4.84 (d, 2H), 5.31-5.45 (m, 1H), 9.01 (s, 1H).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (8.21 g, 50 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (250 mL). The mixture was stirred for 10 min. Quinidine (17.84 g, 55 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (6.08 mL, 150 mmol) was added. The mixture was stirred at −55° C. for 18 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (300 mL). After shaking, the layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (9.15 g, 46.6 mmol, 94%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.4 Hz), 1.33 (1H, d, J=8.4 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.29 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([C@H:22]3[O:9][CH2:8][C@H:5]([CH2:4][CH2:3][CH2:2][F:1])[CH2:6][O:7]3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OCC(CO)CCCF
Reactant: O=Cc1ccc(-c2ccc(F)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FCCC[C@H]1CO[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)OC1

Procedure:
A mixture of 0.1 m of 2-(3-fluoropropyl)-1,3-propanediol, 0.1 m of p-(3,4-difluorophenyl)benzaldehyde (prepared by cross-coupling as described above), 1 g of p-toluenesulfonic acid and 200 ml of toluene is boiled for 1 hour on a water separator. Extractive work-up and purification by crystallization and chromatography give trans-2-(3,4-difluorobiphenyl-4'-yl)-5-(3-fluoropropyl)-1,3-dioxane.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:6])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>C(O)(=O)C.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH:6][C:20](=[O:22])[CH3:21])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 4-bromo-2-nitro-6-[(phenylmethyl)oxy]aniline (33.0 g, 102 mmol, WO 2004054984) and acetic anhydride (14.5 mL, 153 mmol) in acetic acid (90 mL) was added concentrated sulfuric acid (2 drops) at 70° C. The mixture was stirred at 70° C. for 20 minutes. After cooling to room temperature, water (800 mL) was added, and the formed precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound as a brown solid (30.9 g, 83%).
Reaction SMILES: BrCCC[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[S:6]1(=[O:23])=[O:22].[Br:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:24][CH2:25][CH2:26][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[S:6]1(=[O:23])=[O:22]
Reactant: OCCBr
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(Cl)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccc(Cl)cc1F
Yield: 34.4 %

Procedure:
To a stirring solution of 1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (150 mg, 0.502 mmol), 2-bromoethanol (71 uL, 1.00 mmol), and triphenylphosphine (263 mg, 1.00 mmol) in anhydrous tetrahydrofuran was added diisopropylazodicarboxylate (195 uL, 1.00 mmol) and the solution stirred, capped, at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-25% ethyl acetate in hexane to afford 0.07 g of 1-(2-bromoethyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Sn](CCCC)CCCC)CCC.Cl[C:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])([CH3:23])[CH:21]=[O:22]>C1(C)C=CC=CC=1>[O:22]1[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])([CH3:23])[CH:21]1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(Cl)(C=O)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2Cl)OC1n1ccnc1
Yield: 43.7 %

Procedure:
A mixture of tri-n-butyltin imidazole (9.28 g), 2-chloro-2-(2,4-dichlorophenyl)propionaldehyde (4.75 g) and toluene (100 ml) was heated under reflux for 5 hours. After cooling, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The oily residue was purified by chromatography over silica gel to give 1-[1,2-epoxy-2-(2,4-dichlorophenyl)propyl]imidazole (2.35 g, yield 43.7%) as an oil. The product was dissolved in ether, and the ether solution was neutralized by adding fuming nitric acid to give crystals of 1-[1,2-epoxy-2-(2,4-dichlorophenyl)propyl]-imidazole nitrate, which were recrystallized from methanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[S:26][C:25]([O:27][CH2:28][CH3:29])=[N:24][CH:23]=3)[S:21][C:14]=12>>[CH2:28]([O:27][C:25]1[S:26][C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:19]=2)=[CH:23][N:24]=1)[CH3:29]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CCOc1ncc(-c2cc3nccc(Cl)c3s2)s1
Product: CCOc1ncc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)s1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-(2-ethoxy-thiazol-5-yl)-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ10.95 (s, 1H), 8.62 (s, 1H), 8.23 (d, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.33 (m, 2H), 6.88 (d, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 4.44 (q, 2H), 2.46 (s, 3H), 1.35 (t, 3H); RP18-HPLC RT: 5.83 minutes; API MS: 407 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O>ClCCl>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)[N:1]=[C:21]([OH:20])[N:22]=1
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (26.7 g, 0.10 mol) in dichloromethane was treated with sodium cyanate (17.1 g, 0.26 mol) and then trifluoroacetic acid (20.9 ml, 0.26 mol) was added dropwise to the resulting mixture at room temperature. After 45 minutes, the mixture was diluted with dichloromethane (11) and stirred for a further 18 hours. The mixture was then concentrated under reduced pressure and partitioned between methanol and 2N aqueous sodium hydroxide and stirred for 2 hours. The methanol was then removed under reduced pressure and the yellow solid isolated by filtration, washing sequentially with water, acetone and diethyl ether to afford the subtitle compound as a yellow solid (18.0 g, 54%). A further quantity of product was obtained by concentration of the filtrate, acidification with concentrated hydrochloric acid (95 ml), warming on a steam bath for 5 minutes, cooling and neutralisation with solid potassium carbonate. The solid obtained was isolated by filtration, washing sequentially with water, ethanol and diethyl ether to afford the subtitle compound as a yellow solid (12.11 g, 93% combined yield). Rf 0.23 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 298 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37].[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41].C(N(CC)CC)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[O:25][C:40](=[O:41])[NH:27][N:26]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(=O)NN)C1c1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2n[nH]c(=O)o2)C1c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 343 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 6.9 ml of THF was cooled to 0° C., and 116 mg of 1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were added thereto, followed by stirring at 0° C. for 2 hours, and then stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 221 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:7][CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl>CCCCC>[Br:1][C:9](=[CH:8][O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: BrBr
Reactant: CCCCOC=CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CCCCOC=C(Br)C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
8.0 g (0.05 mole) of bromine, dissolved in 100 ml pentane, are added dropwise to a solution of 9.75 g (0.05 mol) of 4-n-butoxy-1,1,1-trifluorobut-3-en-2-one in 50 ml of pentane cooled to -20° C. After stirring for 1 hour at -20° C., a solution of 6.0 g (0.06 mole) of triethylamine in 100 ml pentane is added dropwise at the same temperature. After being allowed to stand overnight at 25° C., the mixture is poured into ice water and acidified by means of 1N hydrochloric acid and the phases are separated. Conventional work-up gives 12.1 g of almost homogeneous crude 3-bromo-4-n-butoxy-1,1,1-trifluorobut-3-en-2-one, which is freed from the small amount of impurities by distillation under reduced pressure. Boiling point 113°-115° C./16 mbar, nD20 =1.4640.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([O:36]C(OCC3C=CC=CC=3)=O)[C@:12]2([F:48])[CH3:47])=[C:4]([O:49][CH3:50])[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[C@@H:13]([OH:36])[C@:12]2([F:48])[CH3:47])=[C:4]([O:49][CH3:50])[N:3]=1
Reactant: [H][H]
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(N[C@@H](C)C(=O)OC(C)C)Oc2ccccc2)[C@@H](OC(=O)OCc2ccccc2)[C@@]1(C)F
Agent: [Pd]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(N[C@@H](C)C(=O)OC(C)C)Oc2ccccc2)[C@@H](O)[C@@]1(C)F

Procedure:
To a solution of crude phosphoramidate 116 in MeOH (2.5 mL) was added 5% Pd on charcoal (40 mg). The atmosphere in the flask was exchanged with hydrogen twice. The mixture was stirred at ambient temperature under one atmosphere of hydrogen for 1 h. The mixture was filtered through a short pad of Celite and the filtrate was concentrated. The crude residue was checked by 1H-NMR and 31P-NMR and ratio of two isomers was ca. 17:1 favored the desired SP isomer (117) and also matched the Sp isomer by thin layer chromatography. 31P-NMR (DMSO-d6): δ 4.91.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:30])=[N:12][N:11]=1.O>CN(C=O)C>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[NH:11][N:12]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(N1CCCC1=O)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 40 °C
Yield: 53.5 %

Procedure:
A solution of 2-pyrrolidinone (0.14 ml, 1.83 mmoles) in dry DMF (10 ml) under N2 was added with NaH (0.068 g, 1.7 mmoles; 60% in oil) and the mixture was heated to 40° C. for 1 hour, cooled and added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45. The mixture was heated to 80° C. overnight, then poured into water (10 volumes) and extracted three times with ethyl acetate. The organic phase was discoloured with charcoal, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 9:1). The resultant solid was triturated in ethyl ether and 0.306 g of the title compound were yielded (yield: 53%). m.p.: 223-225° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cncc(C#N)c1
Reactant: Fc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2cccc(F)c2)c1
Temperature: 80 °C
Yield: 73 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (390 mg, 0.56 mmol), copper (I) iodide (211 mg, 1.11 mmol), and 5-ethynylnicotinonitrile (1.50 g, 11.7 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-fluoro-3-iodobenzene (1.31 mL, 11.1 mmol) in triethylamine (21.6 mL, 155 mmol) and heat to 80° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a 50% saturated aqueous solution of sodium bicarbonate. Back-extract the aqueous layer three times with dichloromethane and twice with ethyl acetate until the aqueous layer is no longer an emulsion. Combine all organic layers and wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Dissolve the residue in ethyl acetate and filter through diatomaceous earth then purify by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane. Further purify by silica gel chromatography, eluting with dichloromethane then 95:5 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (1.8 g, 71%).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][O-:34].[Na+]>CO.C(OCC)(=O)C>[CH3:33][O:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 15 mg, 0.03 mmol) in methanol (1 mL) was added sodium methoxide solution (5.4M solution in methanol, 11 uL, 0.06 mmol) and the reaction mixture was then stirred at 90° C. for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat.NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography to yield the desired product as a white solid (14 mg, 94%). MS (ESI): 486.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:12][NH:13]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: NN
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaldehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at room temperature. The solution was then stirred at 100° C. for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to room temperature. The solid was collected by filtration, washed with water and dried under vacuum to give the indicated product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:5].FC1C=CC(F)=CC=1C(C1C=NC=CC=1C(O)=O)=O.C1COCC1.C>OS(O)(=O)=O.O=S(=O)=O>[F:1][C:2]1[C:3]2[C:4](=[O:5])[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:14])[C:15]=2[C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: C1CCOC1
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Temperature: 25 °C

Procedure:
A solution of the mixture of 4-(2,5-difluorobenzoyl)nicotinic acid and 3-(2,5-difluorobenzoyl)isonicotinic acid of Preparative Example 2 (61.07 g) in 20% oleum (100 mL) is heated at 140° C. while 20% oleum is added in four portions (13.2 mL each) at 20 min-intervals. After the fourth addition the mixture is heated for 20 min, then it is cooled to room temperature and quenched with a mixture of ice (1,500 g), water (1,500 mL) and 35% NaOH (350 mL). The mixture is extracted four times with methylene chloride (1×1,000 mL followed by 3×500 mL). The combined organic solutions are washed with water (2×1,000 mL), dried (Na2SO4) and the solvent removed by roto-evaporation. The dark-red solid obtained (56.0 g) is dissolved in boiling THF (840 mL) and decolorizing charcoal (8.40 g) is added. After 30 min the mixture is filtered while hot and the filtrate concentrated to 200 mL. The precipitate obtained is collected by suction filtration to give 6,9-difluorobenzo[g]isoquinoline-5,10-dione (43.00 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C.N1C=CC=CC=1>[C:25]1([S:31]([NH:1][C:2]2[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 54.7 %

Procedure:
To a stirred solution of benzoic acid 3-amino-4-benzyloxy-phenyl ester (5.91 g, 18.5 mmol) (which was obtained in Example 16) in ethyl acetate (100 mL) and pyridine (20 mL) at 0° C. was added dropwise phenyl sulfonyl chloride (3.26 g, 18.5 mmol) in 50 mL of ethyl acetate. After one hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature over night. The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (4.65 g, 61%); 1H NMR (300 MHz, CDCl3) δ 4.93 (s, 2H), 6.90-7.80 (m, 15H), 8.12 (d, J=8.5 Hz, 2H), 9.81 (s, 1H); MS (ES) m/z: 458.9 (MH+, 100%); HRMS Calcd. for C26H22NO5S(MH+): 459.1141. Found: 459.1151.