Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11](Cl)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4].C(=O)([O-])[O-].[Na+].[Na+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Temperature: 150 °C
Yield: 69 %

Procedure:
A microwave reaction vial was charged with 7-but-3-enyl-2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate B) (96.1 mg, 430 μmol,), ethanol (1.6 mL), a 2M aqueous sodium carbonate solution (645 μL, 1.29 mmol), 4-(trifluoromethyl)phenylboronic acid (98.2 mg, 517 μmol), and tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 23.5 μmol). The reaction was heated in a microwave at 150° C. for 68 min. The reaction was filtered through a pad of Celite®, rinsing with ethanol. The filtrate was concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 10-30% ethyl acetate/hexanes) afforded 7-but-3-enyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (98.9 mg, 69.1%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.59 (q, J=6.66 Hz, 2H) 4.29 (t, J=6.88 Hz, 2H) 4.84-5.21 (m, 2H) 5.58-5.95 (m, 1H) 6.52 (d, J=3.20 Hz, 1H) 7.25 (d, J=3.20 Hz, 1H) 7.90 (d, J=8.29 Hz, 2H) 8.34 (d, J=7.91 Hz, 2H) 12.32 (s, 1H). LC-MS calcd. for C17H15F3N3O [(M+H)+] 334, obsd. 334.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].COB(OC)OC.B(F)(F)F.CCOCC.CO>ClC(Cl)C>[OH:6][CH2:5][C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: COB(OC)OC
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CO)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-hydroxy-4-nitrobenzoic acid (50.0 g, 0.273 mol) in dichloroethane (1000 mL) under a nitrogen atmosphere were added trimethoxyborane (45.4 g, 0.437 mol) and boron trifluoride diethyl etherate (62.0 g, 0.437 mol) followed by dropwise addition of borane-pyridine complex (38.1 g, 0.410 mol). After stirring at room temperature for 4 hours, methanol (100 mL) was added dropwise under cooling in an ice-bath. The mixture was concentrated under reduced pressure and toluene (400 mL) was added to the residue. The resulting mixture was extracted with aqueous 1N NaOH solution (300 mL×3), and the combined aqueous lavers were acidified with conc. hydrochloric acid to pH 1 and extracted with ethyl acetate (500 mL and 300 mL). The organic layers were combined, washed with water (300 mL×2) and brine successively aid dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give B-3 (43.3 g, 94%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9][C:8]=2[N:15]=1)([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9][C:8]=2[N:15]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc2cnc(CO)cc2s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)Nc1nc2cnc(C=O)cc2s1
Reaction time: 1.75 h
Yield: 162.4 %

Procedure:
To a solution of (2-(isopropylamino)thiazolo[4,5-c]pyridin-6-yl)methanol (0.1063 g, 0.476 mmol, 1.0 eq.) in THF (5 mL) under nitrogen was added MnO2 (0.6441 g, 7.4 mmol, 15.6 eq.). After 1.75 hr, the reaction solution was filtered through Celite and rinsed with THF. The filtrate was concentrated in vacuo to give crude 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carbaldehyde as a yellow solid (0.1711 g). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([F:50])([F:49])[F:48])[CH2:43][CH2:42]3)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([F:49])([F:48])[F:50])[CH2:43][CH2:42]3)=[O:40])=[CH:35][CH:34]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-2-one (Preparation 22) (0.548 g, 0.78 mmol) and TBAF (1.55 ml, 1.55 mmol) in 15 ml of dry THF. Stir at room temperature for 2 hours. Quench with saturated NaHCO3 extract with ethyl acetate. Wash with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.448 g (97%) of the title compound: Mass spectrum (apci) m/z=596 (M+H).
Reaction SMILES: S(=[C:3]1[CH:11]=[C:7]([C:8]([Cl:10])=[O:9])[C:6](N)=[C:5]([C:13]([Cl:15])=[O:14])[CH2:4]1)=O.C([NH2:18])=O>CCOCC>[ClH:10].[NH2:18][C:3]1[CH:11]=[C:7]([C:8]([Cl:10])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:13]([Cl:15])=[O:14]
Reactant: NC=O
Reactant: NC1=C(C(=O)Cl)CC(=S=O)C=C1C(=O)Cl
Solvent: CCOCC
Product: Cl
Product: Nc1cc(C(=O)Cl)cc(C(=O)Cl)c1

Procedure:
5.0 g of 5-sulfinyl amino isophthaloyl chloride (Example 1) was dissolved in 150 ml of ether, and anhydrous hydrogen chloride gas was bubbled through for 2 hours. Beige colored precipitate, which weighed 3.71 g after filtration, was obtained. This product was soluble in an amide solvent, such as N,N'-dimethyl acetamide or formamide. However, solution NMR of this product could not be obtained, since it polymerizes in those solvents. Elemental analysis calculated as C8H6NO2Cl3 : Theory: C:37.76, H:2.38 N:5.50. Found C:40.98 H:2.74, N:6.33.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10]=2[CH:11]=1.S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:19])=[O:13])[C:10]=2[CH:11]=1
Reactant: CO
Reactant: O=C(O)c1cccc2cnc(Cl)cc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cnc(Cl)cc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 20 mL microwave vial was charged with 3-chloroisoquinoline-5-carboxylic acid (1 g, 4.82 mmol) in 5 mL of MeOH and then was added with thionyl chloride (0.703 mL, 9.63 mmol). Stirred at 65° C. overnight and then concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded Methyl 3-chloroisoquinoline-5-carboxylate (26-1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])([CH3:40])([CH3:39])[CH3:38]>CO.ClCCl>[C:37]([NH:41][C:42](=[O:45])[CH2:43][CH2:44][NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: C=CC(=O)NC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCC(=O)NC(C)(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.48 mmol) was dissolved in stirred methanol (10 ml) and N-(tert-butyl)acrylamide (62 mg, 0.48 mmol) added. The reaction mixture was stirred for 24 hr at room temperature and then heated at reflux for 120 hr, at which time all solvent had evaporated. The residual reaction mixture was dissolved in dichloromethane and the solvent removed under reduced pressure, this procedure was repeated twice more and then the product purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (143 mg) as a foam. MS: 618 (MH+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:1](=[C:10]1/[C:9](=[O:14])[CH2:13][CH2:12][CH2:11]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCC1
Product: O=C1CCC/C1=C\c1ccccc1

Procedure:
The procedure was similar to that in Example 4 by reacting benzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-benzylidene cyclopentanone. The melting point of this intermediate compound was determined to be 67°-69° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-benzylidene cyclopentanone hydrochloride. The melting point of the product was determined to be 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].CCOC(C)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (PharmaBlock) (2.000 g, 10.69 mmol) in pyridine (15.0 mL) was added 4-dimethylaminopyridine (Aldrich) (0.131 g, 1.069 mmol) and methanesulfonyl chloride (2.5 mL, 32.1 mmol). The resulting mixture was heated to 100° C. under N2 for 2 h. Reaction was cooled to rt. The reaction mixture was poured into the beaker which filled with EtOAc (50 ml) and hand stirred for 10 minutes. The organic layer was decanted into a round-bottom flask. The original mixture (black paste) was dissolved into DCM (3 ml) followed by adding EtOAc (20 ml) and hand stirred for 10 min and decanted to the same round-bottom flask that was mentioned earlier. The combined organic layers were concentrated in-vacuo. The crude product was purified by column chromatography (120 g, 10% to 20% acetone in hexanes) to afford the desired product as light brown solid (1.1 g). MS (ESI pos. ion) m/z: 342.8. 1H NMR (300 MHz, CDCl3) δ ppm 2.64 (s, 3H) 3.47 (s, 6H) 7.73 (d, J=2.05 Hz, 1H) 8.67 (d, J=2.05 Hz, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH3:17][CH:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C:20](Cl)=[O:21]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Solvent: CC(Cl)Cl
Product: CC(CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3)CC(C)(C)C
Yield: 100.5 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 3,5,5-trimethylhexanoyl chloride (0.14 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (15 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3,5,5-trimethylhexanamide (0.25 g). MS (ESI) m/z 356 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[F:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[CH:28][C:27]=1[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH2:26][CH2:25]1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 131 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9, 2.5 Hz), 7.36–7.31 (m, 2H), 7.23–7.17 (m, 1H), 6.93 (t, 2H, J=8.4 Hz), 6.87 (t, 1H, J=8.9 Hz), 6.73–6.68 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.73–2.65 (m, 1 H), 2.45 (septet, 1H, J=6.7 Hz), 2.30–2.21 (m, 4H), 1.9–1.77 (m, 5H), 1.70–1.63 (m, 3H), 1.56–1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:14][CH2:13][C@H:12]2[C@@:15]3([CH:36]=[CH2:37])[C@H:24]([C@@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:26][C@:6]12[CH2:7][O:8][SiH:9]([CH3:11])[CH3:10])[C:23]1[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=1[CH2:17][CH2:16]3)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H]2[C@@]3(C=C)[C@H]([C@@H](CCCCCO)C[C@]12CO[SiH](C)C)C1C=CC(OC)=CC=1CC3)(C)(C)C.[Br:74]CCCCC[C@H]1C[C@@]2(CO[SiH](C)C)[C@@H](CC[C@@H]2C(C)(C)C)[C@@]2(C=C)[C@H]1C1C=CC(OC)=CC=1CC2>>[Br:74][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C@H:25]1[CH2:26][C@@:6]2([CH2:7][O:8][SiH:9]([CH3:11])[CH3:10])[C@@H:12]([CH2:13][CH2:14][C@@H:5]2[C:1]([CH3:4])([CH3:2])[CH3:3])[C@@:15]2([CH:36]=[CH2:37])[C@H:24]1[C:23]1[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=1[CH2:17][CH2:16]2
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Agent: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCO)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCBr)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
The reaction of 930 mg of alcohol 12 is carried out analogously to the test instructions for the conversion of alcohol 8 into bromide 10. In this way, 975 mg of bromide 13 is obtained as a colorless, viscous oil (GC-MS: m/z theor.: 588, pract.: 588).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:21]([C:22]2[S:23]C(C3NC=NN=3)=C(C3C=CC=CC=3)[N:26]=2)=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.Cl[CH:39]([C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[F:53])=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(O)C>[F:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:45]1[N:26]=[C:22]([C:21]2[C:13]([CH3:12])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[S:23][C:39]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Reactant: Cc1nn2ccccc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1F
Yield: 68.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B (v), ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.09 mmol) produced above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11(vi), the title compound (341 mg, 68%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](OS(C)(=O)=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a solution of tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 1.62 mmol) in dry CH2Cl2 (10 mL) was added Et3N (0.71 g, 7 mmol, 4 eq) at 0 to −5° C. A solution of methanesulfonyl chloride (0.8 g, 7 mmol, 2 eq) in dry CH2Cl2 (5 mL) was added dropwise at the same temperature. The mixture was allowed to warm to rt gradually. TLC showed that the starting material had disappeared. Water (30 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers was washed with 10% aq citric acid, satd aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give tert-butyl (2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-yl-carbamate (0.46 g, 81%), which was used in the next step without purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([N+:16]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>CCO.[NH4+].[Cl-].[Zn]>[NH2:16][C:8]1[CH:7]=[C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])[CH:11]=[CH:10][C:9]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of N-methyl-4-(methylsulfonyl)-3-nitrobenzenesulfonamide (1.5 g, crude) in EtOH (20 mL) and saturated aqueous NH4Cl (20 mL) was treated with Zn dust (3.3. g, 51 mmol) and stirred at 50° C. overnight before being filtered (EtOAc wash). The filtrate was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried (MgSO4), concentrated, and subjected to flash chromatography (33% EtOAc-petroleum ether) to give 3-amino-N-methyl-4-(methylsulfonyl)benzenesulfonamide (950 mg, 94% 2 steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=8.28 Hz, 1 H), 7.58 (q, J=4.94 Hz, 1 H), 7.34 (d, J=1.76 Hz, 1 H), 7.01 (dd, J=8.53, 1.76 Hz, 1 H), 6.48 (s, 2 H), 3.18 (s, 3 H), 2.47 (d, J=5.02 Hz, 3 H). MS (m/z) 265.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35](N(CC)C1N=C(C(O)=O)C=C(C)N=1)[CH3:36].C(N)(=O)C>>[CH2:32]([N:31]([CH2:35][CH3:36])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Agent: CC(N)=O
Product: CCN(CC)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-diethylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=1.01 min; [M+H]+=485.30. 1H NMR (D6-DMSO): δ 1.18 (t, J=6.8 Hz, 6H), 2.34 (s, 6H), 2.43 (s, 3H), 3.25 (m, 1H), 3.45 (m, 1H), 3.67 (q, J=6.8 Hz, 4H), 3.70-3.82 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.96 (m, 1H), 5.29 (d, J=5.3 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.27 (s, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.76 (s, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH2:66])[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1>C1COCC1>[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH:66][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
A solution of HATU (98.0 mg, 0.260 mmol), triethylamine (55.7 μl, 0.400 mmol) and 4-trifluoromethyl-benzoic acid (49.0 mg, 0.260 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give title compound as a white solid (TFA salt, 27 mg, 28%). 1H NMR (DMSO-d6, 400 MHz) δ 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H), 3.70 (s, 3H), 3.84-3.87 (m, 2H), 4.39 (t, J=5.05 Hz, 2H), 6.31 (d, J=1.77 Hz, 1H), 7.28 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.75 (d, J=2.78 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.84 Hz, 2H), 8.89 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2, found 475.4 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(COc2cccc(C(=O)O)c2C(=O)O)cc1

Procedure:
A stirred solution of 3-(4-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.0 g crude, 5.5 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (35 mL) was refluxed for two hours. The solution was evaporated in vacuo, and the residue was dissolved in water (80 mL) and washed with methylene chloride (3×70 mL), then acidified to pH around 4 by HCl. The resulting mixture was extracted with ethyl acetate (2×60 mL), and the combined organic layers was washed with water (2×70 mL), dried, and concentrated in vacuo to give 3-(4-methoxy-benzyloxy)-phthalic acid as an off-white solid (1.6 g, 100% crude yield). The product was used in the next step without further purification.