Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:52][C@H:53]([C:58]([O:60][CH2:61][CH2:62][O:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[C:75]([C:76]#[N:77])=[C:74]([N:78]3[CH2:82][CH2:81][CH2:80][CH2:79]3)[N:73]=[C:72]([S:83][CH2:84][C:85]3[N:86]=[C:87]([C:90]4[CH:95]=[CH:94][C:93]([Cl:96])=[CH:92][CH:91]=4)[S:88][CH:89]=3)[C:71]=2[C:97]#[N:98])=[CH:66][CH:65]=1)=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:52][C@H:53]([C:58]([O:60][CH2:61][CH2:62][O:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[C:75]([C:76]#[N:77])=[C:74]([N:78]3[CH2:82][CH2:81][CH2:80][CH2:79]3)[N:73]=[C:72]([S:83][CH2:84][C:85]3[N:86]=[C:87]([C:90]4[CH:95]=[CH:94][C:93]([Cl:96])=[CH:92][CH:91]=4)[S:88][CH:89]=3)[C:71]=2[C:97]#[N:98])=[CH:68][CH:69]=1)=[O:59])[CH2:54][CH:55]([CH3:56])[CH3:57])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1

Procedure:
80 mg (0.45 mmol) of N-(tert-butoxycarbonyl)glycine were initially charged in 5.0 ml of DMF, and 95 mg (0.49 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 95 mg (0.62 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 267 mg (2.06 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred until a clear solution had been obtained. 330 mg (0.41 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-leucinate trifluoroacetate were then added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was added to 300 ml of water. The residue formed was filtered off with suction and washed with 20 ml of water. The crude product was suspended in 15 ml of methanol and sonicated in an ultrasonic bath for 5 min. The residue was filtered off with suction and washed with 10 ml of diethyl ether. This gave 0.17 g (47% of theory) of the desired target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([O:10][C:11]([CH:28]2[CH2:30][CH2:29]2)([C:24]([F:27])([F:26])[F:25])[C:12]#[C:13][Si](C(C)C)(C(C)C)C(C)C)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:11]([CH:28]2[CH2:29][CH2:30]2)([C:24]([F:25])([F:26])[F:27])[C:12]#[CH:13])=[O:9])=[CH:31][CH:32]=1)([O-:3])=[O:2]
Reactant: CC(C)[Si](C#CC(OC(=O)c1ccc([N+](=O)[O-])cc1)(C1CC1)C(F)(F)F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(OC(=O)c1ccc([N+](=O)[O-])cc1)(C1CC1)C(F)(F)F

Procedure:
To a solution of crude 1-cyclopropyl-1-(trifluoromethyl)-3-(triisopropylsilyl)prop-2-yn-1-yl 4-nitrobenzoate from Step 3 (˜8.14 mmol) in THF (30 mL) at room temperature was added a THF solution of tetrabutylammonium fluoride (1.0 M, 9.77 mL, 9.77 mmol). After 1.5 h the reaction mixture was poured in H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (toluene/hexane 40:60 to 60:40) affording the title compound. 1H NMR (400 MHz, acetone-d6): 8.44 (d, 2H), 8.29 (d, 2H), 3.64 (s, 1H), 1.53 (m, 1H), 1.26 (m, 1H), 0.88 (m, 2H), 0.78 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=2[F:22])=[C:4]([O:23][CH3:24])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:21][C:16]1[C:15]([F:22])=[C:14]([C:10]2[N:9]([CH2:8][C:5]3[N:6]=[N:7][C:2]([C:30](=[O:32])[CH3:31])=[CH:3][C:4]=3[O:23][CH3:24])[CH:13]=[CH:12][N:11]=2)[C:19]([F:20])=[CH:18][CH:17]=1
Reactant: COc1cc(Cl)nnc1Cn1ccnc1-c1c(F)ccc(Cl)c1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)=O)nnc1Cn1ccnc1-c1c(F)ccc(Cl)c1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To the mixture of 6-chloro-3-[2-(3-chloro-2,6-difluoro-phenyl)-imidazol-1-ylmethyl]-4-methoxy-pyridazine (95 mg, 0.256 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (139 mg, 1.5 eq.) in toluene (5 mL)is added PdCl2(PPh3)2 (10 mg, 0.05 eq.). The mixture is heated at 110° C. in a sealed tube for 24 hours. On cooling, water (2 mL) and con. HCl (2 mL) are added and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with aqueous NaOH and extracted with DCM. The combined organic layers are dried and solvent removed. The crude product is purified by PTLC (5% methanol in DCM) to give the title compound (20 mg): LC-MS (M+1) 379.1 (retention time: 0.99 minutes).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCN(Cc4ccccc4)C3)cc2F)cc1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-fluoro-phenylamine (400 mg, 1.48 mmol) and 4-isopropylphenylsulfonyl chloride (324 mg, 1.48 mmol) were dissolved in tetrahydrofuran (25 ml). Triethylamine (0.62 ml, 4.44 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (30% conversion). Small portions of 4-isopropyl-phenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). This procedure was repeated until complete conversion was observed. The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (170 mg, 21%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=C(C3N=C(N4CCOCC4)C4SC(CN5CCN(S(C)(=O)=O)C(CO)C5)=CC=4N=3)C=CC=2)[CH:22]=N1.[H-].[Na+].IC>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][O:19][CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(CO)C1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
Amine preparation: to a THF (5 mL) solution of 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, described for the production of 174) was added sodium hydride (0.043 g). The reaction mixture was stirred for 20 min and then iodomethane (0.19 mL) was added. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methanesulfonyl-3-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.254 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]#[N:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:17][CH2:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>>[CH3:20][N:19]1[CH2:21][CH2:22][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)([C:13]#[N:14])[CH2:17][CH2:18]1
Reactant: N#CCc1csc(-c2ccccc2)n1
Reactant: CN(CCCl)CCCl
Agent: Cl
Product: CN1CCC(C#N)(c2csc(-c3ccccc3)n2)CC1
Yield: 25 %

Procedure:
This compound was synthesized from (2-phenyl-thiazol-4-yl)-acetonitrile and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step 1b (135 mg, yield 25%). 1H NMR (300 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.45-7.43 (m, 3H), 7.30 (s, 1H), 3.00-2.96 (m, 2H), 2.53-2.40 (m, 7H), 2.25-2.20 (m, 2H). MS (ESI) m/z: Calculated for C16H17N3S: 283.11. found: 284.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][NH2:10]>CO.[Pd]>[CH3:9][NH:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: CN
Agent: [Pd]
Solvent: CO
Product: CNCc1ccccn1
Reaction time: 2 h

Procedure:
A solution of 2-picolinaldehyde (107.11 g, 1 mol, a severe irritant) in 100 mL of methanol was added to 50 mL of methylamine, and the solution was shaken under N2 for 2 hours. Pre-wetted 10% Pd/C (2.5 g) in 20 mL MeOH was added to the first solution, and the mixture was shaken under 4 arm of H2 for 5 hours. The solution was filtered, the filter cake washed with methanol (2×100 mL), and the solution was filtered through a nylon membrane filter and concentrated in vacuo. Toluene was added, and the solution was concentrated in vacuo to afford 122 g of the title product as an orange oil; bp 80°-82° C.@8 mm Hg. NMR (CDCl3) δ:2.00 (bs,1H), 2.49 (s,3H), 3.88 (s,2H), 7.18 (m, 1H), 7.32 (d,1H), 7.65 (dt,1H), 8.56 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.C(O)(=O)C.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
652 mg of 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoic acid was dissolved in 10.0 mL of THF, and 6.00 mL of a 1 M borane-THF complex was added thereto under an argon atmosphere, followed by stirring at room temperature for 4 hours. To the reaction liquid was added 1.00 mL of a mixed solution of water-acetic acid (1:1) and added water, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 467 mg of N-(3-chloro-2-methylphenyl)-4-(hydroxymethyl)benzenesulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>[Pd].O.C(Cl)Cl.O1CCOCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3ccc4[nH]ncc4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
5-bromo-1H-indazole (21 mg, 0.087 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (50 mg, 0.13 mmol), Fibercat palladium catalyst (Johnson-Matthey, 2.5 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (2 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 50 Watts and 80 C for 10 minutes. The reaction was then cooled to room temperature, and more Fibercat palladium catalyst (8 mg) was added, along with 2 M Na2CO3 (0.25 ml). The reaction was heated in the microwave at 100 C and 75 Watts for 10 minutes, and then re-cooled to room temperature. The reaction was then diluted with water and methylene chloride, and the organic layer was separated, dried over sodium sulfate, filtered, concentrated, and treated with methylene chloride to afford a precipitate. This suspension was filtered, and the solid was collected to afford the title compound (14 mg, 44%). MS (ESI pos. ion) m/z: 370 (M+H). Calc'd Exact Mass for C22H15N3OS: 369.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOP(=O)(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and diethyl chlorophosphate (360 mg, 2.1 mmol) were dissolved in acetonitrile (15 ml), and potassium carbonate (430 mg, 3.1 mmol) was added thereto. The mixture was stirred at room temperature for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (8:1, v/v) were collected, concentrated and recrystallized from diisopropyl ether-methanol to give the titled compound (225 mg, 53%) as white crystals.
Reaction SMILES: O=[C:2]1[CH2:14][C@@H:13](O)[C@H:12]([CH2:16][CH2:17][CH2:18][CH:19](O)[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][OH:11].C=CCCCCC[C@@H]1[C@@H](CCCCCCCC)CCC1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>N1C=CC=CC=1.CO>[CH:10]([OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][C@@H:3]1[C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:14][CH2:2]1
Reactant: CCCCC(O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC=CC=CO
Agent: C=CCCCCC[C@H]1CCC[C@@H]1CCCCCCCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCC[C@H]1CCC[C@@H]1CC=CC=CC=CO

Procedure:
Treatment of the 9-oxo-11α,16-dihydroxy prostadien-1-ol or prostene of Table 8 below with acetic anhydride in pyridine followed by potassium acetate in methanol according to Example 83 furnishes the product 9-oxo-16-hydroxy-Δ10 prostadien-1-ol or prostatrien-1-ol of the table.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.O>CN(C)C=O.C(Cl)(Cl)Cl>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2cnccc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g of 1,6-naphthyridin-2(1H)-one in 10 mL of N,N-dimethylformamide, 0.30 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 0.78 mL of 2-bromomethyl-1,3-dioxolan, and the reaction mixture was stirred at 90 to 100° C. for 30 minutes. Thereto were further added 0.30 g of 60% sodium hydride and 0.78 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 90 to 108° C. for 5 hours 30 minutes. The reaction mixture was cooled to room temperature, water and chloroform were then added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.60 g of 1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36]>O1CCCC1.C(Cl)(Cl)Cl.C(O)(C)C>[CH2:16]([O:15][C:13](=[O:14])[C:11]1[CH:12]=[C:2]([O:1][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=2[N+:35]([O-:37])=[O:36])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[O:18][C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:33])([F:34])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36])[CH3:17]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OCC)cc1Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of diethyl 2,5-dihydroxyterephthalate (127 mg, 0.5 mmol) and sodium hydride (60%, 20 mg) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 30 minutes followed by the addition of 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (75 mg, 0.26 mmol). After 45 mintues, more 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (63 mg, 0.22 mmol) was added. Tetrahydrofuran (1 mL) was added after each addition of 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene. After 18 hours at room temperature, more 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (75 mg) was added and the temperature was increased to 60° C. for 2 hours. The reaction was diluted with chloroform/isopropanol, washed with brine and purified on silica gel to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 8.82 (d, J=2.2 Hz, 2H), 8.27 (dd, 2H), 8.18 (s, 2H), 7.48 (d, J=9 Hz, 2H), 4.15 (q, J=6.8 Hz, 4H), 0.98 (t, J=6.8 Hz, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@H:11]([CH2:28][C:29]#[N:30])[CH2:10]1)(=[O:8])=[O:7].S1C=CC=C1S(N1CCN(C2C=CC([C@](O)(C)C(F)(F)F)=CC=2)[C@@H](CC#N)C1)(=O)=O.S1C=CC=C1S(N1CCN(C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)[C@@H](CC#N)C1)(=O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C@:21]([OH:27])([CH3:26])[C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=2)[C@H:11]([CH2:28][C:29]#[N:30])[CH2:10]1)(=[O:7])=[O:8]
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CC#N)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC#N)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC#N)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CC#N)cc1)C(F)(F)F

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; ((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile; ((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetonitrile. 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 1H), 7.62-7.60 (m, 1H), 7.48-7.46 (d, J=8.8 Hz, 2H), 7.19-7.17 (m, 1H), 6.87-6.85 (d, J=8.8 Hz, 2H), 4.11-4.04 (m, 2H), 3.89-3.78 (m, 2H), 3.48-3.41 (m, 2H), 3.27-3.20 (m, 1H), 2.77-2.72 (m, 1H), 2.69-2.61 (m, 1H), 1.74 (s, 3H). m/z (ESI, +ve ion) 460.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.03 μM; GK-GKRP EC50 (LC MS/MS)=3.94 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([C:16](OC)=[O:17])[C:5]=3[C:4]=2[CH:3]=1.[BH4-].[Na+].CO.Cl>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:14]=[C:15]([CH2:16][OH:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(Cl)ccc1n2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c2ccc(Cl)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Yield: 93.6 %

Procedure:
A solution of 17.2 g (47 mmol) of methyl 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate, of 8.7 g (230 mmol) of sodium borohydride and of 9.4 ml (230 mmol) of methanol in 300 ml of tetrahydrofuran is heated at reflux for 4 h. The mixture is cooled and poured onto a stirred solution of 100 ml of 2N hydrochloric acid and 100 ml of dichloromethane. The precipitate is collected by filtration, washed with water and dichloromethane and dried under reduced pressure. 15 g (44 mmol) of solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[NH:19][CH3:20].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.IC>CO>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:19]([CH3:20])[C:3]3[CH:4]=[C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=4)[CH:17]=[CH:18][C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(NC)c2)ccn1
Solvent: CO
Solvent: CI
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Br)cc4)n(C)c3c2)ccn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and preparative chromatography gave (4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide. MS: MH+=452.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:6])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(NC(C)=O)c2)c1
Yield: 84.8 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (216.0 mg, 0.45 mmol) and acetic anhydride (0.051 ml, 0.54 mmol), the procedure of Inventive Example 97 was repeated to obtain 197.5 mg (84.9%) of the title compound in a colorless amorphous form.