Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1ccc2cccnc2c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc3cccnc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and quinolin-7-ol: 1H-NMR (CDCl3) δ 8.96 (1H, m), 8.60 (1H, d, J=2.8 Hz), 8.24–8.14 (3H, m), 8.00–7.88 (4H, m), 7.47–7.26 (4H, m), 5.39 (1H, m), 3.89 (3H, s), 1.60 (3H, d, J=7.0 Hz).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[NH:24]C(=O)OC(C)(C)C)[C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:12]([C:11]1[NH:24][C:17]2[C:16]([C:10]=1[CH2:9][C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1)=[CH:21][CH:20]=[C:19]([O:22][CH3:23])[CH:18]=2)([CH3:14])[CH3:13]
Reactant: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 93.3 %

Procedure:
To a solution of tert-butyl {2-[1-(6-cyanopyridin-2-ylmethyl)-3-methyl-2-oxobutyl]-5-methoxyphenyl}carbamate (269 mg) in dichloromethane (13 mL) was added trifluoroacetic acid (2.6 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.75 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (181 mg). 1H-NMR (CDCl3) δ ppm: 1.28 (6H, d, J=7.0 Hz), 3.21-3.35 (1H, m), 3.83 (3H, s), 4.26 (2H, s), 6.73 (1H, dd, J=2.3, 8.8 Hz), 6.86 (1H, d, J=2.3 Hz), 7.19-7.29 (2H, m), 7.45-7.52 (1H, m), 7.55-7.64 (1H, m), 7.80 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[Br:22]C(F)(F)C(F)(F)Br>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.ClCCl>[Br:22][C:3]1[C:2]([Cl:1])=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccccc1-c1nnc2cc(Br)c(Cl)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
Tetrabutylammonium difluorotriphenylstannate (6.8 g, 10.8 mmol) was added to a suspension of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (3.17 g, 9.88 mmol), prepared as in Example 25 Step c), and 1,2-dibromotetrafluoroethane (6.0 ml, 50 mmol) in anhydrous THF (75 ml) and the mixture was stirred at room temperature under nitrogen for 18 h. The mixture was diluted with dichloromethane (100 ml), filtered and the filtrate was concentrated. Flash column chromatography on silica gel, eluting with 50-100% EtOAc-hexane, gave 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (2.84 g, 88%) as an off-white solid; 1H NMR (360 MHz, CDCl3) δ7.31 (1H, dd, J=10 and 10 Hz), 7.36 (1H, ddd, J=8, 8 and 1 Hz), 7.57-7.63 (1H, m), 7.87 (1H, ddd, J=7, 7 and 2 Hz), 8.49 (1H, s); MS (ES+) m/e 327/329/331 [MH]+.
Reaction SMILES: C[O:2]C(=O)C1C=CC=CC=1N.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.O=S(Cl)Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:21])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)Cc1ccc(F)cc1

Procedure:
First, 2-amino-benzoic acid methyl ester (1.00 g, 6.61 mmol) was dissolved in purified CH2Cl2, and DMAP (0.04 g, 0.33 mmol) was added thereto at 0° C. Then, the mixture was added to the reaction vessel containing (4-fluorophenyl)-acetyl chloride produced from reaction of (4-fluoro-phenyl)-acetic acid (1.53 g, 9.90 mmol) with SOCl2, and then reacted at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, and then concentrated under reduced pressure to obtain 1.50 g (79%) of the compound 2-[2-(4-fluorophenyl)-acetylamino]-benzoic acid methyl ester as the solid.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:23]([O:26][CH2:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][N:39]([CH:4]5[CH2:5][O:1][C:2](=[O:6])[CH2:3]5)[CH2:40][CH2:41]4)=[C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OCC4CCCC4)cc23)cc1Cl
Reactant: O=C1C=CCO1
Solvent: CO
Product: O=C1CC(N2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OCC3CCCC3)CC2)CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
46 mg of (5H)-furan-2-one are added to a solution of 230 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-[2-(piperazin-1-yl)-ethoxy]-quinazoline in 2 ml of methanol. The reaction mixture is stirred for 24 hours at ambient temperature, then for another six at 50° C. In total, six more drops of (5H)-furan-2-one are added until the reaction is complete. The solvent is distilled off using the rotary evaporator and the crude product is purified by chromatography over an Alox column (activity stage III) with methylene chloride/methanol (98:2) as eluant. The desired product is obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)CC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 53.6 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (prepared as in Example 1(a)) (200 mg) and 4-piperidineacetic acid, ethyl ester (305 mg). The reaction mixture was evaporated to dryness, the residue was suspended in methanol and the solid collected by filtration to afford the sub-title compound (150 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:16]1C=CC=CN=1>>[CH3:16][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([C:7]2([C:13]#[N:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:3]=1
Reactant: N#CC1(c2ccccn2)CCNCC1
Reactant: Fc1ccccn1
Product: Cc1ccnc(C2(C#N)CCNCC2)c1

Procedure:
4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile was prepared by the procedure described for the synthesis of 4-pyridin-2-ylpiperidine-4-carbonitrile in Example 1, substituting 2-fluoro-4-methylpyridine for 2-fluoropyridine.
Reaction SMILES: Cl[CH:2]1[C:14](=[O:15])[C:13]2[C:12]3[C:7]4=[C:8]([O:16][CH2:17][CH:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:6]4[C:5]=2[CH2:4][CH2:3]1)[CH:9]=[CH:10][CH:11]=3.[Li+].[Cl-]>CN(C=O)C>[C:19]1([CH:18]2[N:6]3[C:7]4[C:12]([C:13]5[C:5]3=[CH:4][CH:3]=[CH:2][C:14]=5[OH:15])=[CH:11][CH:10]=[CH:9][C:8]=4[O:16][CH2:17]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 68.1 %

Procedure:
A mixture of 8-chloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.235 g, 0.697 mmol), anhydrous LiCl (0.0355 g, 0.837 mmol), Li2CO3 (0.0618 g, 0.837 mmol), and DMF (1.8 mL) is stirred at 140° C. for 3.5 h. After cooling, the mixture is partitioned between CH2Cl2 and water. The organic layers are dried over sodium sulftate, concentrated, and chromatographed on silica gel gel using EtOAc/hexane (10/90) to give 0.143 g (68%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 86 %

Procedure:
To a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (5 g, 24 mmol) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (4.78 g, 23.9 mmol, 1 eq.) and potassium carbonate (9.9 g, 72 mmol, 3 eq.). The resulting mixture was stirred with heating overnight at 100° C. (oil bath) and then diluted with water (300 ml). The solids were collected by filtration to afford tert-butyl 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a yellow powder (8 g, 86%); (ES, m/z): [M+H]+ 390.0; 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=9.3 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.89 (dd, J=2.4, 9.3 Hz, 1H), 3.87 (d, J=13.5 Hz, 2H), 3.68 (m, 1H), 2.95 (m, 2H), 2.54 (s, 0.6H), 1.89 (m, 2H), 1.39 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C1(C)C=CC=CC=1.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 15 g of pyrazole and 200 ml of toluene was added dropwise 23.7 ml of dimethylsulfamoyl chloride at room temperature. Then, 40 ml of triethylamine was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 17.6 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=[O:24])C>O1CCCC1.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(OCC(C)(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (4.0 g.) in dry tetrahydrofuran (60 ml.) was added dropwise to a stirred solution of mercuric acetate (6.35 g.) in water (60 ml.) and the solution stirred at room temperature for one hour. Sodium hydroxide solution (40 ml., 3 N) and sodium borohydride (0.75 g.) in sodium hydroxide solution (40 ml., 3 N) were then added dropwise to the stirred solution at 0° C. The grey suspension was stirred at 0° C. for one hour, glacial acetic acid was added to pH 6, then the suspension filtered and the filtrate extracted with chloroform (3×150 ml.). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (2.1 g.). This product in methanol (30 ml.) and sodium hydroxide solution (20 ml., 5 N) was heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3×20 ml.), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g.) as an oil. A sample was characterized as the oxalate salt which recrystallized from ethyl acetate and had an m.p. of 132°-134° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1>CS(C)=O>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][CH2:29][CH2:28][NH:27][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:32]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCCCc1c[nH]c2ccccc12
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCCCc2c[nH]c4ccccc24)CO3)N1
Temperature: 75 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino-[2,3-e]indol-8-one (1.5 g, 4.2 mmole) in DMSO (80 ml) was slowly added through a dropping funnel to 3-(3-aminopropyl)indole (1.1 g, 6.3 mmole) in DMSO (50 ml) and the mixture was heated at 75° C. for 17 hours. Most of DMSO was removed under reduced pressure and the residue was then partitioned between water and dichloromethane/isopropanol (3/1) solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using first ethyl acetate/hexane (7/3), then ethyl acetate and finally 5% methanol in ethyl acetate as eluants. The expected product was isolated, treated with 0.25M ethanolic fumaric acid and precipitated with a minimum amount of hexane to give 70 mg of the (S) enantiomer of the title compound as a tan solid fumarate salt, Mass spec (m/e), 377 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH:19]=O>>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH2:19][C:10]1[S:11][C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Reactant: O=Cc1c(F)cccc1Cl
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3c(F)cccc3Cl)sc12
Yield: 4.3 %

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)thieno[2,3d]pyridazin-4(5H)one (example 6 step b 1.00 g) and 2chloro-6-fluorobenzaldehyde (0.96 g) according to the is procedure of Example 14. The crude product was purified by preparative normal-phase HPLC with gradient dichloromethane/ethanol elution followed by recrystallisation from isohexane to give the title compound (0.07 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O.N>>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:17]1[C:15]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3][C:4]=2[CH:16]=1
Reactant: Nc1ccccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1-c1ccccc1
Temperature: 160 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
A 2-neck flask (20 mL) equipped with reflux condenser was charged with 2-methyl-1-phenylbenzimidazole-5-carboxylic acid (see Synthesis Example 1-3) (0.15 g, 0.59 mmol), 2-aminophenol (0.09 g, 0.82 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 160° C. and stirred under those conditions for 20 hours. After being allowed to cool to room temperature, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. The precipitated crystals were filtered off, these were washed with distilled water (approx. 3 mL, 2 times), and then dried to yield the title compound (0.13 g, 68% yield) as greenish pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH3:40])([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:37]([C:34]3([CH3:40])[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]3)=[O:38])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 25 mg, 0.075 mmol), 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (22 mg, 0.090 mmol), and HATU (34 mg, 0.090 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.039 mL, 0.23 mmol) was added to the reaction dropwise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 80% acetonitrile/water to yield the final product as a yellowish powder (28 mg, 67% yield). MS (apci) m/z=557.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([CH2:18][NH:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([C:2]([F:1])([F:39])[F:38])[CH2:18][NH:19][C:20]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:13]=1
Reactant: COc1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.9 %

Procedure:
1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol (Example 22, 46 mg, 0.085 mmol) was dissolved in anhydrous dichloromethane (4 ml) and cooled to −70° C. (cardice/acetone bath). Boron tribromide (1.0M in dichloromethane, 0.15 ml, 0.15 mmol) was added and the mixture allowed to warm to room temperature over 2 hours and then stirred for a further 20 hours. The mixture was cooled to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 20 hours. The mixture was cooled again to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 32 hours. The mixture was then diluted with dichloromethane (15 mL), cooled in ice and quenched with methanol (3 mL). After a further 15 min the mixture was partitioned between dichloromethane (35 mL) and aqueous sodium bicarbonate (35 mL). The organic phase was washed again with aqueous sodium bicarbonate (35 mL), passed through a hydrophobic frit and evaporated under reduced pressure to yield crude material. This crude product was purified by mass-directed autopreparation to give the title compound (9 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+]>C1COCC1.C(O)C>[OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cc3)c(O)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 400 mg (0.92 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate with 336 mg (8.4 mmol) of sodium hydroxide in a THF/ethanol mixture (20 ml/20 ml), 214 mg (58%) of a pink powder are obtained. m.p.=217° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([O:15]CC)=[O:14])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12](=[O:18])[C:13]([OH:15])=[O:14])[CH3:11]
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a 3 L volume four-necked flask, ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a) (320.82 g) and tetrahydrofuran (600 ml) were added at room temperature and cooled. 10.7% by weight of aqueous sodium hydroxide solution (900 ml) was added dropwise at 10° C. over 2 hours. The resulting mixture was stirred at room temperature for 1 hour. After the organic solvent was removed under reduced pressure, tert-butyl methyl ether was added to the aqueous layer to wash. After the organic layer was removed, to the aqueous layer was added dropwise concentrated hydrochloric acid (180 ml), and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 166.55 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetic acid (8-a).