Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[S:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.I[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[S:15][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=S)c12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Yield: 83 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thione (4.04 g, 13.8 mmol), 1-iodopropane (6.80 mL, 69.7 mmol) and potassium carbonate (3.79 g, 27.5 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 8 hours. The reaction solvent was evaporated under reduced pressure. Water was added to the residue, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate/hexane to give the title compound (3.83 g, 83% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16].C(COC)OC.CCCCCC>C(OCC)C.[Zn]>[C:5]([O:4][CH2:1][CH:2]1[CH2:3][C:15](=[O:16])[C:14]1([Cl:19])[Cl:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCOC(=O)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: O=C(OCC1CC(=O)C1(Cl)Cl)c1ccccc1
Yield: 37.1 %

Procedure:
To a suspension of benzoic acid allyl ester (100 g, 0.617 mol) and zinc (activated Zn) (161 g, 2.47 mol) in diethyl ether (1.23 L) was added dropwise a solution of trichloroacetyl chloride (223 g, 1.23 mol) and dimethoxyethane (110 g, 1.23 mol) in diethyl ether (1.23 L, 2 L/mol) over 40 minutes under nitrogen with vigorously stirring, and then the mixture was stirred at room temperature (internal temperature: 30° C.) for 29 hours. During the stirring, additional zinc (activated Zn) (respectively, 150 g (2.29 mol) and 100 g (1.53 mol)) was added at 7 and 24 hours after the beginning of the stirring. To the reaction mixture was added hexane (1 L), and the mixture was stirred for 10 minutes, and then the solid was removed by decantation and the supernatant was washed with water (1 L), aqueous saturated sodium bicarbonate solution (3×1 L) and saturated saline (500 mL), and dried over magnesium sulfate. The mixture was evaporated and the precipitated white solid was collected by filtration and washed with hexane (500 mL) to give the titled compound (62.5 g, 37%).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][OH:29])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:31])[CH2:4][CH2:5][C:6](=[O:30])[CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>N1C=CC=CC=1>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:31])[CH2:4][CH2:5][C:6](=[O:30])[CH:7]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOS(C)(=O)=O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 0.80 g of 9-fluoro-16α-(2-hydroxyethoxy)-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 10 ml of pyridine is stirred with 0.5 ml of methanesulfonyl chloride for 90 minutes at 0°C under nitrogen. The solution is poured into cold 5% hydrochloric acid and extracted with chloroform. The chloroform extract is dried and evaporated to give an oil which is chromatographed on a 20 g -- silica gel column. Elution with chloroform gives 521 mg of TLC pure 9-fluoro-16α-(2-mesyloxyethoxy)-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([C:34]3[CH:33]=[N:32][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc(-c2ccc(OCc3ccccc3)cc2)nn1
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCc4ccccc4)cc3)nn2)cn1
Yield: 69.3 %

Procedure:
In accordance with scheme D, 14 g (47.2 mmol) of 6-chloro-3-(4-benzyloxyphenyl)pyridazine are reacted analogously to Example 4a with 11.8 g (47.2 mmol) of 2-octyloxypyridine-5-boronic acid to give 15.3 g of 3-(4-benzyloxyphenyl)-6-(6-octyloxypyridin-3-yl)pyridazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1OC
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3,4-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (d, 1H, J=3.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H, J=2.4 and 8.4 Hz), 7.00-6.90 (m, 4H), 6.80 (d, 1H, J=8.1 Hz), 6.40 (m, 1H), 4.05 (q, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.20 (t, 3H); 19F NMR (CD3OD): −47223; LCMS: ret. time: 17.94 min.; purity: 99%; MS (m/e): 357 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25][CH2:24]3)[N:10]=2)=[C:4]([F:31])[CH:3]=1.C(OC([N:39]1[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41]([OH:43])=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]([CH3:30])[C:41](=[O:43])[C@@H:40]4[CH2:44][CH2:45][CH2:46][NH:39]4)[CH2:27][CH2:28]3)[N:10]=2)=[C:4]([F:31])[CH:3]=1
Reactant: CNC1CCN(c2nc(Nc3ccc(Cl)cc3F)c3cc(OC)c(OC)cc3n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(4-chloro-2-fluorophenyl)-6,7-dimethoxy-2-[4-(methylamino)piperidin-1-yl]quinazoline-4-amine (445 mg), 1-(tert-butoxycarbonyl)-L-proline (323 mg), HOBt (135 mg) and EDCI hydrochloride (290 mg) were added in that order to DMF (10 mL), followed by stirring at room temperature for 24 hours. Ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution, and the organic layer was separated. Next, the organic layer was washed with saturated brine, dried over magnesium sulfate and then filtered. The solvent was evaporated under a reduced pressure. By purifying the residue by silica gel flash column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide was obtained. This was dissolved in ethyl acetate (10 mL), and 4 M HCl/ethyl acetate solution (0.5 mL) was added thereto. By evaporating the solvent under a reduced pressure and recrystallizing the resulting residue from EtOH-diethyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (481 mg) was obtained as pale yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:30])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH:13]=2)=[N:6][N:7]=1)[CH3:2].[CH3:32][S-:33].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([S:33][CH3:32])=[CH:10][C:11]([CH3:30])=[C:12]([CH:13]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:6][N:7]=1)[CH3:2]
Reactant: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2SC)[nH]1
Temperature: 110 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a round-bottom flask was added a solution of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 258.2, 20 mg, 0.050 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL). Sodium thiomethoxide (70 mg, 0.10 mmol, 2.0 equiv) was added to the reaction. The resulting mixture was stirred for 15 h at 110° C. in an oil bath, and then cooled to ambient temperature and quenched with 100 mL of ice water. The mixture was extracted with 50 mL of ethyl acetate and the combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (37% CH3CN up to 49% in 7 min, up to 100% in 3 min, down to 37% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 4 mg (19%) of the title compound as a white solid. m/z (ES+) 446 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.35 (br s, 1H), ˜4.85 (1H partially obscured by water peak), 3.77-3.60 (m, 1H), ˜3.3 (1H partially obscured by methanol solvent peak), 3.08-2.94 (m, 2H), 2.91 (q, J=7.7 Hz, 2H), 2.51 (s, 3H), 2.47 & 2.37 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.10-1.97 (m, 1H), 1.88-1.55 (m, 3H), 1.40 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: CO
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 24 h
Yield: 98.3 %

Procedure:
A 500 ml autoclave was charged in a glove box with 2 g (6.73 mmol) of (Z)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)isoquinoline (prepared according to any one of Examples 1-4), 170 ml of methanol and 1.3 mg (0.0017 mmol; S/Ru =4000) of Ru(CH3COO)2 (BIPHEMP) as the catalyst. The hydrogenation was carried out at 100° C. and 35 bar for 24 hours. The hydrogenation solution was evaporated and the residue was dissolved in diethyl ether. After separation of the catalyst over silica gel and evaporation of the filtrate, there were obtained 1.98 g of (S)-2-acetyl-1 -(p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline of 98.3% e.e., which was recrystallized from diisopropyl ether. [α]D20 =+53° (c=1 in CH3OH); 100% e.e., m.p. 80°-81.5° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][C@H:7]([CH2:9][OH:10])[CH2:6][O:5]1.S(OC)(O[CH3:16])(=O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.ClCCl>[CH3:16][O:10][CH2:9][C@@H:7]1[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC[C@@H]1COC(C)(C)O1
Temperature: 20 °C
Yield: 113.1 %

Procedure:
Into a 6 liter reactor equipped with a condenser, a temperature probe and a dropping funnel are introduced 420 ml of demineralized water and 420 g (10.5 mol) of sodium hydroxide pellets. To the solution, stirred at 20° C., are added 2.3 l of dichloromethane, 396 g (3.00 mol) of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol ([α]D20 =-11°; c=4; methanol) and 20.5 g (0.090 mol) of benzyltriethylammonium chloride. 567 g (4.50 mol) of dimethyl sulfate are then added in the course of 50 min, while keeping the temperature below 30° C. The mixture is stirred for 18 hours and then 1 liter of water is added. The organic phase is separated and washed with 0.5 l of water. The aqueous phases are reextracted with 3 l of dichloromethane and then the organic phases are combined, filtered and concentrated by distillation under reduced pressure. 496 g of product are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NC1CCC(CCO)CC1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.102 g, 0.34 mmol) was reacted with 2-(4-aminocyclohexyl)ethanol (0.140 g, 1.0 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.006 g, 4%) as a white solid. MW=407.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.48 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.71-7.51 (m, 3H), 7.09 (s, 1H), 4.34 (br s, 1H), 3.85-3.82 (m, 1H), 3.45 (t, J=6.0 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.91-1.85 (m, 2H), 1.78-1.73 (m, 2H), 1.46-1.32 (m, 5H), 1.16-1.05 (m, 2H); APCI MS m/z 371 [M+H]+.
Reaction SMILES: [I-].[K+].Cl[CH2:4][CH2:5][CH2:6][C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1.[CH3:13][C:14]12[C:22](=[O:23])[CH2:21][CH2:20][CH:19]1[CH:18]([O:24][CH2:25][CH:26]=[O:27])[C:17](=[O:28])[CH2:16][CH2:15]2.O>CN(C=O)C.C1C=C2C3[N-]C(C2=CC=1)=NC1=NC(C2C1=CC=CC=2)=NC1=NC(C2C1=CC=CC=2)=NC1[N-]C(=C2C=1C=CC=C2)N=3.[Co+2].[Cr](Cl)(Cl)=O>[OH:27][CH:26]([CH2:4][CH2:5][CH2:6][C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1)[CH2:25][O:24][CH:18]1[C:17](=[O:28])[CH2:16][CH2:15][C:14]2([CH3:13])[CH:19]1[CH2:20][CH2:21][C:22]2=[O:23]
Reactant: CC1(CCCCl)OCCO1
Reactant: CC12CCC(=O)C(OCC=O)C1CCC2=O
Agent: O=[Cr](Cl)Cl
Agent: [Co+2]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CCCC(O)COC2C(=O)CCC3(C)C(=O)CCC23)OCCO1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Potassium iodide (31.1 g, 187.5 mmol, 3 eq) was added to a solution of 2-(3-chloro-propyl)-2-methyl-[1,3]dioxolane (18.8 mL, 125 mmol, 2 eq) in DMF (50 mL) and the reaction mixture was stirred at 60° C. in dark for 6 h. The reaction mixture was then cooled to room temperature and then combined with (7a-Methyl-1,5-dioxo-octahydro-inden-4-yloxy)-acetaldehyde (14 g, 62.5 mmol) in DMF (150 mL). To the stirred mixture at 0° C., was added cobalt phthalocyanine (357 mg, 0.625 mmol, 0.01 eq), followed by chromous chloride (23.1 g, 187.5 mmol, 3 eq) portion-wise, resulting in release of heat. The reaction mixture was allowed to stir from 0° C. slowly to room temperature for 24 h. The reaction mixture was then cooled to 0° C. and cold water (200 mL) was added. The resulting mixture was extracted with pentane (200 mL). The aqueous layer was extracted with dichloromethane (4×200 mL). The combined organic layer was dried with magnesium sulfate, filtered, the solvent was removed together with toluene (2×100 mL) under reduced pressure, and the resulting residue purified by flash chromatography 20-70% ethyl acetate in hexane to yield the tile compound as an oil, as 1:1 mixture of two diastereomers.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.Cl[C:23]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[S:24].C(N(CC)CC)C.C(NCC)C>O1CCCC1>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[O:25][C:23]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]2[CH2:7][CH2:6][C:3]3([CH2:4][CH2:5]3)[C@H:2]([OH:1])[CH2:9]2)[C:15](=[O:21])[C@@H:16]1[CH3:20])=[S:24]
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Reactant: C[C@@H]1NCCN(CCCCN2CCC3(CC3)[C@H](O)C2)C1=O
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=S)Oc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one (intermediate 27; 50 mg, 0.17 mmol) in tetrahydrofuran (0.5 mL) was added at 0° C. O-2-naphthyl chlorothioformate (38 mg, 0.17 mmol) and triethylamine (17 mg, 0.17 mmol). The ice bath was removed, then after 20 min the reaction mixture was cooled to 0° C. and treated with diethylamine (6 mg, 90 μmol), then concentrated under vacuum. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) furnished the title compound (52 mg, 64%). Orange oil, MS (ISP)=482.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:16])=O.Cl.S(=O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(OCC(=O)O)ccc1Cl
Agent: Cl
Agent: O=S=O
Product: Cc1cc(OCC(=O)Cl)ccc1Cl
Yield: 84.8 %

Procedure:
In a 100 ml round bottom flask equipped with a reflux condenser, 27 g of 3-methyl-4-chlorophenoxyacetic acid and 32 g of thionyl chloride were charged and a small amount of zeolite was added and the mixture was refluxed until completely dissolving the reaction product. After the reaction, excess of thionyl chloride, and dissolved hydrochloric acid gas and sulfur dioxide gas were removed by a rotary evaporator and the product was distilled to obtain 25.0 g of 3-methyl-4-chlorophenoxyacetic acid chloride. The distillation was carried out at 121° to 125° C. under the pressure of 7 to 8 mmHg. The yield was 80.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)n(-c2ccccc2)n1
Yield: 65.2 %

Procedure:
Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (85 μL, 0.97 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (209 mg, 65%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=4)[N:14]=[C:13]([CH3:22])[C:12]=3[CH3:23])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[CH:10]=[C:2]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:3]=[C:4]([C:24]#[N:25])[C:5]=2[CH:6]=[CH:7]1
Reactant: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(Br)cc32)c1C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(-c4cn[nH]c4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-4-carbonitrile (0.2 g, 0.487 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1134 g, 0.584 mmol) to give 1-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(1H-pyrazol-4-yl)-1H-indole-4-carbonitrile as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (1H, br. s.), 8.23 (1H, br. s.), 8.11 (1H, d, J=9.0 Hz), 8.04 (1H, s), 7.95 (1H, br. s.), 7.83 (1H, d, J=3.2 Hz), 7.75 (1H, dd, J=8.9, 2.3 Hz), 7.45 (1H, s), 6.99 (1H, d, J=3.2 Hz), 6.91 (1H, d, J=2.2 Hz), 2.78 (3H, s), 2.02 (3H, s); Mass Spectrum (ESI) m/e=398.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:6]=1[CH3:38])=[O:4].CO.[OH-].[Li+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[C:6]=1[CH3:38])=[O:4]
Reactant: COC(=O)Cn1nc2n(c1=O)[C@H](c1ccc(C#N)cc1)C(C(=O)OC)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To a solution of Intermediate 25 (240 mg, 0.46 mmol) in THF (3 mL), was added MeOH (3 mL) followed by lithium hydroxide (3M in water, 200 μL, 0.6 mmol). The reaction mixture was stirred at RT for 2 hours, and then the volatiles were removed in vacuo. The resultant residue was dissolved in water, and the solution thus obtained was made acidic by addition of 6 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a colourless oil (250 mg).