Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[N:10]=2)[N:7]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:18][N:19]([CH3:20])[C:12](=[O:14])[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
0.959 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 6 ml of N,N-dimethylformamide; 0.714 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 60 minutes. To this mixture, 0.392 g of dimethylamine hydrochloride and 0.665 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Saline was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (95:5). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration to yield 0.608 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1nc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C(=O)c3ccccc3)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
(3-Hydroxy-quinolin-2-yl)-phenyl-methanone (27 mg), 4-chloro-6,7-dimethoxyquinoline (120 mg), and 4-dimethylaminopyridine (147 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 42%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([I:16])[CH:15]=[C:10]3[N:9]=[C:8]2[NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[O:25][CH3:26].[OH-].[Na+].CC1C=CC(S(O[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)(=O)=O)=CC=1>O1CCCC1.O>[I:16][C:14]1[CH:15]=[C:10]2[N:9]=[C:8]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([O:1][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=4)=[C:3]([O:25][CH3:26])[CH:4]=3)[C:11]2=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(C(F)(F)C(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-36-1) (0.24 g, 0.52 mmol) in tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.2 mLs, 1.00 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (10 mL). The mixture was treated with 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate (0.40 g, 1.04 mmol), and the mixture was warmed to 80° C. After 3 h, the mixture was allowed to cool to room temperature and was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 0.090 g of ethyl (6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:24](=[S:25])[N:23]([C:26]3[CH:27]=[C:28]([C:34]([F:37])([F:36])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=3)[C:22](=[O:38])[C:18]32[CH2:21][CH2:20][CH2:19]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N:17]3[C:24](=[S:25])[N:23]([C:26]4[CH:27]=[C:28]([C:34]([F:36])([F:37])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=4)[C:22](=[O:38])[C:18]43[CH2:19][CH2:20][CH2:21]4)=[CH:3][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCCN4CCNCC4)c(F)c3)C2=S)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCOc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A mixture of 5-(5-(3-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 174, 50 mg, 0.1 mmol), acetic anhydride (13 μL, 0.14 mmol), and triethylamine (40 μL, 0.27 mmol) in DCM (2 mL) was stirred at room temperature for 2 days. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford 34 mg of 5-(5-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.74 (s, 1H), 7.42 (t, 1H), 7.35 (dd, 1H), 7.22 (m, 1H), 4.28 (t, 2H), 3.42 (m, 4H), 2.80 (t, 2H), 2.65-2.59 (m, 2H), 2.54-2.44 (m, 6H), 1.98 (m, 4H), 1.57 (m, 1H). LCMS [M+1]+ 591.9.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:5]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1.O>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:8]=[N:9][C:4]([CH2:1][CH2:2][CH2:3][OH:35])=[CH:5][C:6]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: C=CCc1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc(CCCO)nnc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.3 %

Procedure:
To a solution of 6-allyl-3,4-bis(4-methoxyphenyl)pyridazine (0.58 g, 1.7 mmol) in tetrahydrofuran (3 ml), a 0.5 M solution (8.7 ml) of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran was added dropwise under an argon gas atmosphere while cooling the reaction system with ice-water. The resulting mixture was then stirred at room temperature for 15 hours. To the reaction mixture, water (1 ml) and then, 3 N caustic soda (3 ml) and 31% hydrogen peroxide (3 ml) were added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and was then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure and the resulting mixture was left over at room temperature for 3 days. The residue was separated and purified by chromatography on a silica gel column (ethyl acetate), whereby the title compound was obtained as a pale brown oil (0.54 g, 88.3%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:9])[CH3:8].Br[CH2:29][C:30]1[C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:33]([C:51]([F:54])([F:53])[F:52])=[CH:32][CH:31]=1.O>CN(C)C=O>[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]2[C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:33]([C:51]([F:52])([F:53])[F:54])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cesium carbonate (209 mg, 0.644 mmol) was added to a solution of methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.429 mmol) obtained in Example (40-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (181 mg, 0.429 mmol) obtained in Example (28-5) in N,N-dimethylformamide (4 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to give tert-butyl 6-[({2′-acetyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (93 mg, yield: 34%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.C(N1CCNCC1)C1C=CC=CC=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:45][C:42]2[C:43](=[O:44])[N:38]([CH2:37][CH:34]3[CH2:35][CH2:36]3)[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)[CH:41]=2)[CH2:13][CH2:12]1)[C:19]1[CH:18]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: c1ccc(CN2CCNCC2)cc1
Product: COc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a yellow oil (yield: 97.7%).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([NH:70][CH:71]([CH3:73])[CH3:72])[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:82]2[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=2)O1>>[CH:71]([NH:70][C:69]1[C:64]2[S:63][CH:62]=[C:61]([C:82]3[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=3)[C:65]=2[N:66]=[CH:67][N:68]=1)([CH3:73])[CH3:72]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(C)Nc1ncnc2c(Br)csc12
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CC(C)Nc1ncnc2c(-c3ccc(O)cc3)csc12

Procedure:
The title compound 69B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 69A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.49 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.88-7.91 (m, 2H), 7.57 (d, J=7.67 Hz, 1H), 6.83-6.86 (m, 2H), 4.44-4.53 (m, 1H), 1.25 (d, J=6.75 Hz, 6H). ESI (+)/MS: 286 (M−H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[C:36]=1[OH:42])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[C:33]([C:35]1[C:36]([OH:42])=[C:37]([CH:38]=[CH:39][CH:40]=1)[NH:41][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:34])[CH3:32]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 2.4 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (50 ml) was added to a stirred solution of 3-amino-2-hydroxyacetophenone (1.5 g) and pyridine (0.9 g) in dry methylene chloride (40 ml) at 10° C. After standing at room temperature overnight, the solution was evaporated in vacuo and the resulting solid residue was recrystallised from a large volume of ethanol to give 3'-acetyl-1-benzyl-2'-hydroxy-1H-tetrazole-5-carboxanilide (1.5 g), in the form of pale yellow needles, m.p. 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:22]([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)cc1
Yield: 10.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.016 g).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Br[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[CH:26]=[C:19]3[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]3=[N:17]2)=[C:11]([Cl:27])[CH:10]=1.C(Cl)(Cl)Cl>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:1]=[CH2:2])[CH:10]=[C:11]([Cl:27])[C:12]=1[N:16]1[CH:26]=[C:19]2[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]2=[N:17]1
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(Br)cc3Cl)cc2c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Triethylamine (3.5 mL, 25 mmol) was added to a mixture of 2-(4-bromo-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.88 g, 5.0 mmol), potassium vinyl trifluoroborate (1.0 g, 7.5 mmol) and Pd(dppf)Cl2.CHCl3 (408 mg, 0.5 mmol) in propan-1-ol (50 mL) and the reaction mixture was heated at 100° C. for 1.5 hours. The resultant mixture was allowed to cool to room temperature before being partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a beige solid (1.0 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (d, J=2.6 Hz, 1H), 8.89 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.3, 1.5 Hz, 1H), 7.97 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.24 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]NC(=O)[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.Cl.[CH3:33][N:34]([CH:36]=[O:37])[CH3:35]>>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:16])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:33][N:34]([CH3:35])[C:36](=[O:37])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)C1(C)CN(C)C(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-7-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (500 mg, 1.34 mmol) in anhydrous DMF at 0° C. were added sodium hydride (35 mg, 1.47 mmol, 95% dispersion in oil) and iodomethane (100 μL, 1.61 mmol). The reaction was stirred for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous 3N HCl (447 μL, 1.34 mmol) and partitioned between EtOAc and H2O. The aqueous layer was extracted several times with EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated to a yellow residue. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a clear oil. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.47 (m, 2H), 7.43-7.31 (m, 3H), 5.20 (dd, J=11.2, 39.6 Hz, 2H), 4.19-4.11 (m, 2H), 3.98 (q, J=13.6 Hz, 2H), 3.80 (s, 3H), 2.99 (s, 3H), 1.81 (s, 3H), 1.13 (t, J=7.2 Hz, 3H); ES MS (M+H)=402.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:24])=O)=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 52e (light pink powder), which was used in the next reaction without further purification.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:18]2[C:27]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:26]([CH:40]([CH3:42])[CH3:41])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:45])[CH2:21][C:22]([CH3:44])([CH3:43])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[C:12]1([C:18]2[C:27]([C:28]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)=[O:39])=[C:26]([CH:40]([CH3:41])[CH3:42])[CH:25]=[C:24]3[C:19]=2[CH:20]([OH:45])[CH2:21][C:22]([CH3:43])([CH3:44])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
80 μl (450 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.51 mg (17 μmol) of (1R,2S)-1-aminoindan-2-ol in 2.6 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 53 mg (112 μmol) of 5-cyclohex-1-en-1-yl-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethyl)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 37A) in 2.6 ml of tetrahydrofuran is slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 20:1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cc(COC2OCCNC2c2ccccc2)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN1CCOC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 150 mg (0.37 mmol) of the trans-isomer of (+/−)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl morpholine (Example 4) and 0.18 mL (1.00 mmol) of N,N-diisopropyl-ethyl- amine in 2 mL of acetonitrile was treated with 0.095 mL (1.00 mmol) of methyl bromoacetate and the resulting solution was stirred at rt for 20 h. The solution was concentrated in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 5 mL of 0.5 N aqueous potassium hydrogen sulfate solution. The layers were separated; the organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 164 mg (93%) of the trans-isomer of the title compound as an oil: 1H NMR 2.79 (dt, 1H, J=3.2, 11.2), 2.93 (dt, 1H, J=11.2, 1.6), 3.52 (d, 1H, J=7.2), 3.63 (s, 3H), 3.92 (dt, 1H, J=2.8, 11.6), 4.04 (ddd, 1H, J=11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2H, J=13.2), 4.46 (d, 1H, J=7.2), 7.31-7.38 (m, 6H), 7.68 (s, 1H);