Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]1.[O:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]([C:29](O)=[O:30])=[C:19]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29]([C:20]2[C:21](=[O:22])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:18][C:19]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[CH2:11][CH2:12]1
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(NCCCCN1CCN(c2ccccn2)CC1)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
3.6 g of the 4-[4-(2-pyridyl)-piperazin-1-yl]butylamine obtained above were added to a reaction mixture cooled to -20° C. which contained, in 100 ml of absolute dichloromethane, a mixed anhydride produced in a manner analogous to Example 1 (a) from 4.0 g flavone-3-carboxylic acid, 3.367 g dimethylaminopyridine and 1.28 ml methanesulfonyl chloride. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for two hours. Subsequently the reaction mixture was worked up analogously to Example 3, and the resulting title compound was recrystallized from ethylacetate. There were obtained 4.7 g 3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl)-flavone. yl]-butylaminocarbonyl}-flavone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:13][C:14]1[CH:32]=[C:31]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:30]=[C:29]([CH3:44])[C:15]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][O:27][CH3:28])=[C:21]([CH:24]=1)[CH:22]=[O:23]>C1COCC1>[CH3:44][C:29]1[CH:30]=[C:31]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:40])[CH3:39])[CH:32]=[C:14]([CH3:13])[C:15]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][O:27][CH3:28])=[C:21]([CH:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:23])[CH:24]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirring solution of bromobenzene (0.45 g, 2.89 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.16 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 h and a solution of 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxybenzaldehyde (example 35; step e, 1.2 g, 2.63 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford [5-(2,6-dimethyl-4-triisopropylsilanyloxy-benzyl)-2-methoxymethoxy-phenyl]-phenyl-methanol as an yellow oil (1.4 g, 99.6%): 1H NMR (200 MHz, DMSO-d6): δ 7.23 (m, 6 H), 6.85 (d, J=8.8 Hz, 1 H), 6.68 (m, 1 H), 6.56 (s, 2 H), 5.92 (d, J=4.0 Hz, 1 H), 5.62 (d, J=4.0 Hz, 1 H), 5.10 (q, J=4.0 Hz, 2 H), 3.84 (s, 2 H), 3.23 (s, 3 H), 2.11 (s, 6 H), 1.23 (m, 3 H), 1.06 (d, J=6.4 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=15% ethyl acetate in hexanes; Rf=0.50.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])O[C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:12](=[O:17])[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][C:14]2=[O:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(c3ccc([N+](=O)[O-])cc3)CC2=O)cc1
Temperature: 85 °C
Yield: 669 %

Procedure:
A solution of 12.6 g (53.6 mmol) of 4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in the previous step) in THF (160 mL) was treated with 9.04 mL (6.96 mmol) of 4-methoxy-benzylamine at RT for 2 h. Solvents were evaporated in vacuo. The residue was dissolved in 1.0 N HCl (200 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (1×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was treated with acetic anhydride (200 mL) and triethylamine (30 mL), and heated to 85° C. for 1.5 h. The mixture was concentrated in vacuo, treated with 1.0 N HCl (200 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1×200 mL) and water (1×200 mL), dried (MgSO4), and concentrated in vacuo. The solid was triturated with hexane using sonication, filtered and air-dried to afford 16.5 g (87%) of the title compound as light tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H21N2O, 325.1 (M−OCH3+2H). found 325.0.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[F:17][C:18]1([F:25])[CH2:22][NH:21][C@H:20]([C:23]#[N:24])[CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:21]1[CH2:22][C:18]([F:25])([F:17])[CH2:19][C@H:20]1[C:23]#[N:24])=[O:4]
Reactant: N#C[C@@H]1CC(F)(F)CN1
Reactant: O=C(Br)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a CH2Cl2 solution (5 mL) containing bromoacetyl bromide (365 mg, 1.80 mmol) cooled to −10° C. was added dropwise (2S)-4,4-difluoro2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (described earlier) (500 mg, 1.64 mmol) and triethylamine (199 mg, 1.97 mmol) in CH2Cl2 (5 mL). After stirring for 2 hours at 10° C. the reaction was quenched with H2O and the organics extracted with CH2Cl2 and washed with 1.0 M HCl. After drying over MgSO4 the solvents were reduced in vacuo yielding 400 mg (1.57 mmol, 96% yield) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[NH3:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: N
Product: Nc1nccc(-c2sc(C3CCOC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.100 g, 0.181 mmol) and ammonia (7 N solution in MeOH, 3.88 mL, 27.1 mmol) the title compound was obtained as a light yellow solid (53 mg, 0.099 mmol, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.62-7.79 (m, 1H), 7.40-7.49 (m, 1H), 7.36 (t, J=6.1 Hz, 1H), 7.17-7.33 (m, 3H), 6.78 (br. s., 2H), 5.84 (d, J=5.1 Hz, 1H), 3.96-4.09 (m, 1H), 3.73-3.95 (m, 4H), 2.34-2.47 (m, 1H), 2.05-2.22 (m, 1H). MS (ESI) 534.10 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:29][N:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Cl)cc3)nc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.50 g, 8.45 mM) and 4-chlorophenyl hydrazine (10.60 g, 59.20 mM) in ethanol (50 mL) was added triethylamine (9.43 mL) to give a brown solution. This solution was refluxed for 24 hours and then cooled to room temperature. Dilution with water (25 mL) gave a brown precipitate. This suspension was stirred for 16hours and filtered to remove the solids which were discarded. The filtrate formed another precipitate after standing for seven days. This solid was collected and washed with aqueous methanol (50%) and ether to give the 4-chlorophenyl hydrazine salt of the title compound as a brown powder (1.20 g). This material was refluxed in glacial acetic acid (25 mL) for 3 hours and cooled to room temperature. The resulting orange suspension was filtered, and the solids were washed with glacial acetic acid and ether togive the title compound (0.810 g, 25%) as a light orange powder, mp 399°-401° C.; MS(CI): 374 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH3:49])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.[W]>[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH2:49][Br:1])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nc(C)n(Cc2ccccc2)c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Yield: 74.9 %

Procedure:
2.52 g of N-bromosuccinimide and 0.42 of benzoyl peroxide were added to a solution of 4.07 g of diethyl 1-benzyl-2-methylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 80 ml of carbon tetrachloride, and the mixture was irradiated by a 375 W tungsten lamp for 50 minutes, whilst stirring. At the end of this time, the reaction solution was washed with a 5% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium hydrogencarbonate, in that order, after which it was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.81 g of the title compound as a syrup.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3>[Pd]>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([NH2:22])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccccc1OCC2

Procedure:
5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was hydrogenated in the presence of 10% Pd on carbon to give 231 after reverse phase HPLC. LCMS: 311.2.
Reaction SMILES: [Al].[CH3:2][C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH:6]([C:11](=[O:13])[CH3:12])[CH2:5][CH:4]=1>[Al].C(O)(CC)C>[CH3:2][C:3]1[CH2:8][C:7]([CH3:9])([CH3:10])[CH:6]([CH:11]([OH:13])[CH3:12])[CH2:5][CH:4]=1
Reactant: CC(=O)C1CC=C(C)CC1(C)C
Agent: [Al]
Solvent: CCC(C)O
Product: CC1=CCC(C(C)O)C(C)(C)C1
Reaction time: 8 h
Yield: 56.8 %

Procedure:
9.6 g of aluminium, 2.8 g of aluminium isopropylate, 0.2 g of mercuric chloride and 130 g of secondary butyl alcohol are introduced into a flask and the mixture is brought to reflux. Once the aluminium has started to react, 390 g of secondary butyl alcohol are slowly added over 45 minutes, maintaining reflux. Heating is then dicontinued and the mixture is left to attain the ambient temperature, stirring is discontinued and a calcium chloride drying tube is fitted. The mixture in then left overnight. On the following day, the mixture is brought to reflux and 332 g of 1,5,5-trimethyl-4-acetyl-cyclohex-1-ene are added in the course of about 2 hours. When the vapour temperature reaches 80°, the methyl ethyl ketone formed starts to distill off; the duration of the distillation is about 6 hours--finally under a pressure of 50 mm of mercury. The residue is taken up in 500 ml of benzene and washed twice with 100 ml of 10% sulphuric acid, twice with 100 ml of water, twice with 100 ml of a sodium bicarbonate solution and then with water until neutral. Distillation of the solvent over a water bath under reduced pressure gives 322 g of crude product, which are fractionated in a 500 ml three-necked flask fitted with a 1 meter adiabatic column having an unoxidisable filling with a particle size of 4×4 mm. 190.8 g of 1,5,5-trimethyl-4-(1-hydroxyethyl)-cyclohex-1-ene (57%) are obtained, having the following physical properties:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1.[H-].[Na+].O>CC#N>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:33][C:34]2[CH:35]=[N:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)nc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 example 88) in MeCN (0.5 mL) was added 3-amino-6-(trifluoromethyl)pyridine (77 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 15 min and at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (18 mg, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1. 1.0 mL). The solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 466 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(N)cccc2cn1
Yield: 94 %

Procedure:
To a solution of Example 35A (1.60 g, 8.82 mmol) in ethanol (45 mL) and THF (45 mL) was added 10% Pd/C (100 mg). The solution was hydrogenated under 1 atmosphere of hydrogen for 16 hours at ambient temperature. The mixture was filtered through a plug of Celite and the volatiles were evaporated in vacuo. The resulting solid was triturated with 1:1 CH2Cl2-hexanes and air-dried to provide the title compound (1.31 g, 8.29 mmol, 94% yield) as a light green solid. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.80 (dd, J=7.4, 1.2 Hz, 1H), 5.84 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(C2=CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a round bottom flask containing ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol), sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol (0.617 mL, 15.2 mmol). The mixture was stirred at room temperature overnight. Reaction was quenched via addition of 1N HCl in water (2 mL), then diluted with EtOAc and transferred to reparatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organics were washed with brine, dried over Na2SO4, and filtered, at adsorbed to Celite (10 mL). Column chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM afforded 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; 1H NMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d, J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd, J=5.4, 5.4, 2H), 3.32 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8]C>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)NCCc2ccccc2)cc1F
Solvent: CO
Product: Oc1ccc(CCNCCCCCCNCCc2ccccc2)cc1F

Procedure:
This was prepared from the product of step (a) above (2.68 g) using the procedure of example 3(d) (Method I). The sub-title compound (2.55 g) was obtained as plates from methanol mp 305°-307°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=N[N:31]=[C:30]2N(C)N=C(C3C=CC=CC=3Cl)C=12.C(CC#N)(=O)C1C=CC=CC=1.Cl.N(CC(OCC)=O)N.C(N(CC)CC)C.OC1C=CC=C[N+]=1[O-].Cl.CN.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:31][CH3:30])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CNN
Agent: CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 5 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid, which was synthesised following similar procedures outlined in Example 1 (Compound 37), using benzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile and ethyl hydrazinoacetate hydrochloride and 1.5 equivalent of triethylamine instead of methylhydrazine in Step 1. To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (73 mg, 0.2 mmol) in CH2Cl2 (1 mL) were added 2-hydroxypyridine-N-oxide (HOPO) (22 mg, 0.2 mmol), methylamine hydrochloride (14 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (50 mg, 0.25 mmol), diisopropylethylamine (DIPEA) (90 μl, 0.2 mmol) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 90 min then concentrated in vacuo. The residue was purified by preparative HPLC yielding Compound 5 as an off-white solid (6 mg).
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5].S(Cl)([Cl:24])=O>>[CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1

Procedure:
A mixture of 1.85 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoic acid in 30 ml of thionyl chloride under argon is heated at reflux for 1 hour. The thionyl chloride is evaporated in vacuo to a residue which is stirred with hexane and collected to give 1.94 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoyl chloride which is dissolved in 25 ml of methylene chloride and 0.49 g of N,N-diisopropylethylamine added, followed by 0.65 g of 6,11-dihydro-5H-dibenz[b,e]azepine. The reactants are stirred at room temperature for 18 hours and washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate to give 1.19 g of the desired product as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:16].[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])=[C:3]([F:16])[CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1F
Reaction time: 4 h
Yield: 31.8 %

Procedure:
5-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.31 g, 1.44 mmol) was dissolved in pyridine (3 mL), ethane sulfonyl chloride (0.12 mL, 1.3 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluorophenyl]ethane sulfonamide (0.127 g). HPLC purity 100% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument, 3.5/, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C14H14FN3O2S+H+, 308.08635; found (ESI, [M+H]+), 308.0855.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:2]([F:15])([F:1])[C:3]([F:5])([F:4])[F:6])=[CH:8][CH:9]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1ccc(C(F)(F)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
To a stirred solution of (4-(perfluoroethyl)phenyl)methanol (0.60 g, 2.65 mmol) and triethylamine (0.53 g, 5.30 mmol) in dichloromethane (30 mL) was added p-toluenesulfonyl chloride (1.00 g, 5.30 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated. Chromatographic purification of the residue (silica gel, 10% ethyl acetate in petroleum ether elute) afforded 0.400 g (40%) of 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate as a yellow oil.