Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[N:9]=1)=[O:19])([CH3:25])[CH3:24]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2ccc(F)cn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(5-fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=331.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24 (td, J=7.9, 4.8 Hz, 1H), 1.404 (s, 3H), 1.408 (s, 3H), 2.24-2.30 (m, 1H), 2.74-2.79 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz, 1H), 3.70 (d, J=6.2 Hz, 2H), 4.72 (t, J=6.3 Hz, 1H), 6.92 (s, 1H), 7.55 (ddd, J=9.1, 7.6, 3.0 Hz, 1H), 7.91 (dd, J=9.1, 3.9 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.C1C[O:11][CH2:10]C1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([NH:28][NH2:29])=[O:27])=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]>O>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[O:27][C:10](=[O:11])[NH:29][N:28]=3)=[CH:23][CH:24]=2)[CH:19]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:18][CH:17]1[CH3:38])(=[O:15])[CH3:14]
Reactant: C1CCOC1
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(Cl)cc2)CC1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(Cl)cc2)CC1C
Reaction time: 72 h
Yield: 89 %

Procedure:
Triethylamine (744 μL, 534 μmol) was added to a THF (10 mL) solution of compound 115 (100 mg, 267 μmol) at room temperature, and 1,1′-carbodiimidazole (64.9 mg, 400 μmol) was further added thereto. The resulting mixture was stirred for 3 days at the same temperature. Water was added to the reaction liquid, and the mixture was extracted with chloroform. Subsequently, the organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1-÷ 1:2), and thus 94.8 mg (89%) of the title compound was obtained as a pale yellow amorphous substance (cis:trans=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[Si:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(Cl)c1
Yield: 75 %

Procedure:
A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert-butyl(dimethyl)silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and N,N-dimethylaminopyridine (10 mg) in N,N-dimethylformamide (40 ml) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acteate (100 ml) and water (100 ml). The organic phase was separated, washed with sat. aq. sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Further purification by column chromatography on silica gel eluting with pentane:ethyl acetate (3:1 changing to 2:1) gave the title compound as a colourless oil (6.50 g).
Reaction SMILES: [Mg].[Cu](C#N)C#N.F[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=2)C2OC2)C2OC2)=[CH:10][CH:9]=1.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:14]([O:18][CH2:19][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: Fc1ccc(C(OC(c2ccc(F)cc2)C2CO2)C2CO2)cc1
Agent: N#C[Cu]C#N
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-6enzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(=O)C2CC2)C(=O)c2ccccc2C1=O
Yield: 103.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with cyclopropyl carbonyl chloride (0.07 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (235 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[C@@H:6]([OH:22])[CH2:5]2.O1CCC[CH2:24]1.CI.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[C@@H:6]([O:22][CH3:24])[CH2:5]2
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccc(Cl)cc2C[C@@H]1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a solution of 2-[(1R,2S)-5-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (25.8 g, 0.0822 mol) in tetrahydrofuran (186 mL, 2.29 mol) was added methyl iodide (20.5 mL, 0.329 mol) and the solution was stirred at 0° C. To this solution was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (90.4 mL, 0.0904 mol) dropwise via an addition funnel over 1 hour. The reaction was quenched via addition of 0.1 N HCl (250 mL) and transferred to a separatory funnel containing EtOAc (600 mL). The layers were separated, and the organic layer was washed with 1N NaOH (2×100 mL each) and with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (25.8 g, 96%) which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38](O)=[O:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][CH:38]=[O:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: O=CO
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: O=CNS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 34.8 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.18 mmol) obtained in Example 22 step 5 and formic acid (0.033 mL, 0.89 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.037 g, 34%) was obtained.
Reaction SMILES: C([O-])(=O)C.[Na+].II.[CH3:8][CH2:9][C@@H:10]([OH:57])[C@@:11]([OH:56])([C@@H:13]1[O:26][C:24](=[O:25])[C@H:23]([CH3:27])[C@@H:22]([O:28][C@@H:29]2[O:34][C@@H:33]([CH3:35])[C@H:32]([OH:36])[C@@:31]([O:38][CH3:39])([CH3:37])[CH2:30]2)[C@H:21]([CH3:40])[C@@H:20]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[CH2:45][C@H:44]([N:49](C)[CH3:50])[C@H:43]2[OH:52])[C@:18]2([CH3:53])[O:19][C:15](=[C:16]([CH3:54])[CH2:17]2)[C@@H:14]1[CH3:55])[CH3:12].[OH-].[Na+]>N.O.CO>[CH3:8][CH2:9][C@@H:10]([OH:57])[C@@:11]([OH:56])([C@H:13]1[O:26][C:24](=[O:25])[C@H:23]([CH3:27])[C@@H:22]([O:28][C@@H:29]2[O:34][C@@H:33]([CH3:35])[C@H:32]([OH:36])[C@@:31]([O:38][CH3:39])([CH3:37])[CH2:30]2)[C@H:21]([CH3:40])[C@@H:20]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[CH2:45][C@H:44]([NH:49][CH3:50])[C@H:43]2[OH:52])[C@:18]2([CH3:53])[O:19][C:15](=[C:16]([CH3:54])[CH2:17]2)[C@@H:14]1[CH3:55])[CH3:12]
Reactant: CC[C@@H](O)[C@@](C)(O)[C@@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C
Agent: CC(=O)[O-]
Agent: II
Agent: N
Solvent: CO
Solvent: O
Product: CC[C@@H](O)[C@@](C)(O)[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](NC)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
Sodium acetate (3.9 g, 48.5 mmol) and iodine (2.5 g, 9.7 mmol) were added in this order to methanol (52.0 mL)-water (13.0 mL) solution of EM701 (6.9 g, 9.7 mmol) at room temperature, and stirred at 50° C. for 3 hours. During the stirring, 1N aqueous solution of sodium hydroxide was added to maintain at pH 8-9 continuously. After confirming the completion of the reaction by TLC, the reaction mixture was diluted with aqueous ammonia (7.5 mL)-water (200 mL), and extracted with dichloromethane. After dehydrating the organic layer with sodium sulfate, the sodium sulfate was removed by filtration and distilled off the solvent to obtain crude substance. The crude substance was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM703 (4.8 g, Yield: 70%, white powder). EM703: m. p.: 177-180° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1(C)C(C)=CC=CC=1>[N:31]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:20][C:9]2=3)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)c1c(N3CCCC3)nc(N3CCCC3)nc1n2CCn1ccnc1

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE4, 0.64 g), imidazole (1.02 g) and xylene (15 mL) is heated at reflux for 3 hr. The xylene is then removed under reduced pressure, and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated. Chromatography (silica gel, 4% methanol/methylene chloride) gives the title compound, mp=181°-183°; NMR (CDCl3) 7.88, 7.40, 7.14-7.09, 7.01-6.97, 6.82, 4.56-4.54, 4.44-4.42, 3.92, 3.63 and 1.99 δ.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(#N)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[C:7]1([S:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: NCCN1CCCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(CCNCCN1CCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A mixture of 20.06 g (0.098 mole) of [(2-chloroethyl)sulfonyl]benzene 15.44 g (0.109 mole) of N-(2-aminoethyl)homopiperidine, and 15.0 g (0.149 mole) of triethylamine in 800 ml of acetonitrile was stirred at room temperature for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over magnesuim sulfate, and the solvent waas removed in vacuo to give an oil. This was dissolved in methanol, and the solution was treated with a solution of 2 equivalents of maleic acid (25.52 g, 0.22 mole) in methanol. A white solid precipitated at room temperature to give 32.3 g (60.7%) of title compound as a white solid; mp 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](SC)=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[C:3]([NH:19][NH2:20])=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]
Reactant: CSc1nc(=O)n(Cc2cccs2)c(C)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)c(NN)nc(=O)n1Cc1cccs1

Procedure:
A solution of 5-chloro-6-methyl-4-methylthio-1-(2-thienylmethyl)pyrimidin-2-one (987 mg) and hydrazine hydrate (98-100%) (2.5 ml) in ethanol (50 ml) was stirred and heated at reflux for one hour. The solution was evaporated to a gum which crystallised from ethanol to give pale purple crystals of the title pyrimidinone (649 mg) m.p. 184°-187° C.; λmax (EtOH) 232 nm (ε 14,720), 291.5 nm (ε 10,400).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O1CCOCC1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[N:26]([CH3:25])[CH3:36])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: CN(C)c1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)c1ccccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Yield: 96.7 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (20 g), pyridine (26 g) and dioxane (200 ml) was added dropwise 2-dimethylaminobenzoyl chloride (30 g) under cooling at 0° C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was poured into 500 ml of water, then shaken with additional dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) then once with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was recrystallized with dichloromethane and n-hexane to obtain 7-chloro-2,3-dihydro-l-(2-dimethylaminobenzoyl)-4(lH)-quinolinone (yield 35 g) as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (5.0 g, 27.0 mmol) in 70 mL DCM is added thionyl chloride (12.1 mL, 162 mmol). The reaction mixture is stirred at 50° C. for 1.5 h and overnight at RT. The reaction mixture is concentrated in vacuo, the residue is taken up in fresh DCM and concentrated in vacuo again. Yield: 5.12 g.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[F:40]C1C=CC=C(OC)C=1B(O)O>CCCCCCC.CCOC(C)=O>[F:40][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([O:38][CH3:39])[C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cccc(F)c1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-fluoro-6-methoxyphenylboronic acid (CAS RN 78495-63-3) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (65%). MS (ESI): m/z=233.109 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]1
Reactant: c1cnn(C2CCCCO2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnn1C1CCCCO1
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.10 g, 13.8 mmol) in anhydrous THF (30.0 mL) was added n-BuLi (2.5 M in hexane, 14.0 mL) at −78° C. The mixture was kept at this temperature for 30 min. Triisopropyl borate (2.85 g, 15.2 mmol) was added over 10 min at −78° C. and held for 1 hr. The resulting mixture was allowed to reach room temperature over 4 hr. After being quenched by aq. HCl (2.00 M, 55.0 mL) with intensive stirring, the aqueous phase was added NaCl (s) and extracted with THF/EtOAc. The combined organic layer was washed with brine, sat NaHCO3, dried over MgSO4, filtered and evaporated to afford 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (3.6 g, 52% yield) as yellow oil. LCMS (ESI) m/z: 197.0 [M+H+].
Reaction SMILES: BrC1C=NN2C=C(C3C=NN(C(C)(C)C)C=3)C=C(O[C@@H]([C@H]3CN([C@@H](C4C=CC(OC)=CC=4)C)C(=O)C3)C)C=12.C[Zn]C.[C:42]([N:46]1[CH:50]=[C:49]([C:51]2[CH:52]=[C:53]([O:61][C@@H:62]([C@H:64]3[CH2:68][N:67]([C@@H](C4C=CC(OC)=CC=4)C)[C:66](=[O:79])[CH2:65]3)[CH3:63])[C:54]3[N:55]([N:57]=[CH:58][C:59]=3[CH3:60])[CH:56]=2)[CH:48]=[N:47]1)([CH3:45])([CH3:44])[CH3:43]>Cl.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]>[C:42]([N:46]1[CH:50]=[C:49]([C:51]2[CH:52]=[C:53]([O:61][C@@H:62]([C@H:64]3[CH2:68][NH:67][C:66](=[O:79])[CH2:65]3)[CH3:63])[C:54]3[N:55]([N:57]=[CH:58][C:59]=3[CH3:60])[CH:56]=2)[CH:48]=[N:47]1)([CH3:43])([CH3:44])[CH3:45]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4ncc(C)c34)CC2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4ncc(Br)c34)CC2=O)cc1
Product: Cc1cnn2cc(-c3cnn(C(C)(C)C)c3)cc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Temperature: 75 °C

Procedure:
To an appropriate sized microwave vial, (R)-4-((R)-1-(3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (60 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.7 mg, 0.010 mmol) were added. After evacuating and backfilling with nitrogen, dioxane (1 mL) was added followed by dimethylzinc (0.13 mL, 0.26 mmol, 2M solution in toluene). The mixture was heated at 75° C. for 18 h. After cooling to room temperature, the reaction was diluted with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford a mixture of dehalogenated starting material and title compound (R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methylpyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. The mixture was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H37N5O3: 516.3; found: 516.2.
Reaction SMILES: [CH3:1][S:2]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[N:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])=[O:3].C(OC(C)C)(C)C>[Pd].C(O)C.C1COCC1>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([S:2]([CH3:1])(=[N:4][C:5](=[O:10])[C:6]([F:9])([F:7])[F:8])=[O:3])=[CH:16][CH:15]=1
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc(N)cc1
Reaction time: 0.75 h
Yield: 89 %

Procedure:
292 mg palladium on charcoal (10%/50% moisture) was added to a solution of 1.34 g (4.52 mmol) (RS)-S-methyl-S-(4-nitrophenyl)-N (trifluoroacetyl)sulfoximide in 45 ml ethanol and 8 ml THF and was hydrogenated for 45 minutes under normal pressure at 24° C. The mixture was filtered and concentrated by evaporation. The residue obtained was stirred with diisopropyl ether. The solid was filtered off with suction and dried. 1.07 g (4.03 mmol; yield: 89%) of the product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([O:28]S(C2C=CC=CC=2)(=O)=O)[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.N.Cl>O1CCCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1cc(O)no1
Yield: 102 %

Procedure:
To a solution of 0.5 g of 3-[2-tert-butoxycarbonylamino-3-(3-benzenesulfonyloxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 4 ml of tetrahydrofuran is added 2.5 ml of a methanol solution (6N) of ammonia at room temperature, and they are subjected to reaction at the same temperature for 16 hours. Water and ethyl acetate are added to the reaction mixture, 1N hydrochloric acid is thereafter added to adjust the pH to 2, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 0.38 g of 3-[2-tert-butoxycarbonylamino-3-(3-hydroxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole having a melting point of 158.8°-160.7° C.