Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:15][S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: CSc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: CSc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-(methylthio)aniline (30 μl, 0.243 mmol) similar to Example 13 and isolated as a pink oil (67 mg, 89%). 1H NMR (CDCl3): 8.77-8.74 (m, 1H), 8.44-8.41 (m, 1H), 7.81-7.75 (m, 1H), 7.46 (s, 1H), 7.34-7.28 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.09-7.06 (m, 1H), 7.00-6.97 (m, 1H), 6.55 (d, J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH3:31])[CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH3:31])[CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)NCCN(C)c1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A mixture of 111a (130 mg, 0.186 mmol) and LiOH.H2O (40 mg, 0.93 mmol) in THF/i-PrOH/water (2.0 mL/1.0 mL/1.0 mL) was stirred at rt for 2 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH=20/1) to give 111 (40 mg, 33%) as white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.39-7.35 (t, J=8.4 Hz, 1H), 7.26-7.23 (m, 1H), 7.10-7.08 (m, 1H), 6.64 (s, 1H), 6.18-6.16 (d, J=8.4 Hz, 1H), 6.08-6.00 (m, 2H), 5.85-5.79 (m, 1H), 5.47-5.44 (d, J=10.4 Hz, 1H), 4.30-4.28 (d, J=6.4 Hz, 2H), 4.02-3.99 (t, J=6.4 Hz, 1H), 3.75-3.69 (m, 5H), 3.47-3.45 (m, 2H), 3.02-2.98 (m, 5H), 2.86 (m, 2H), 1.98 (m, 4H). ESI-LCMS: m/z=656 [C34H34FN7O4S+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](C2C=CC3C4CCNC5(CCCOC5)C=4OC=3C=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:29][CH:30]1[C:35]2([C:40]3[O:41][C:42]4[CH:47]=[C:46](I)[CH:45]=[CH:44][C:43]=4[C:39]=3[CH2:38][CH2:37][NH:36]2)[CH2:34][CH2:33][O:32][CH2:31]1.FC1C=C(S)C=CC=1>>[F:29][CH:30]1[C:35]2([C:40]3[O:41][C:42]4[CH:47]=[C:46]([S:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)(=[O:10])=[O:9])[CH:45]=[CH:44][C:43]=4[C:39]=3[CH2:38][CH2:37][NH:36]2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Reactant: FC1COCCC12NCCc1c2oc2cc(I)ccc12
Agent: Fc1cccc(S)c1
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCOCC1F)NCC3

Procedure:
As described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3′-fluoro-7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran] and 3-fluorobenzenethiol The resulting diasteroisomeric mixture was separated using medium pressure liquid chromatography (140 g amine column) eluting with a gradient of EtOAc in hexanes (from 15% to 70% EtOAc).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:8])[CH2:6]Cl)([CH3:3])[CH3:2].[OH-:9].[Na+]>C(O)(C)C>[CH:1]([O:4][C:5](=[O:8])[CH2:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:9])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)OC(=O)CCl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CC(=O)OC(C)C
Yield: 92 %

Procedure:
20 g of Co2 (CO)8 in 2.5 liters of isopropanol and 546 g (4 moles) of chloroacetic acid isopropyl ester are placed in a pressure vessel of a capacity of 18 liters, as in Example 1. At 55° C., and a pressure of 5 bars of CO, a 2.93% solution of sodium hydroxide in isopropanol is pumped into the vessel over a period of 3 hours, maintaining a pH of 7.0. At a transformation of 82%, 615 g of malonic acid diisopropyl ester (92% yield) is obtained after the usual processing. 98 g of chloroacetic acid isopropyl ester is recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:29]([CH3:30])[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccnc(CN(CCCCC=O)C(=O)OC(C)(C)C)c1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CN(CCCCCN(C)C)C(=O)OC(C)(C)C)c1

Procedure:
Prepared by General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](5-oxopentyl)amino}methyl)pyridine-4-carboxylate (1.0 equiv.), dimethylamine hydrochloride (1.2 equiv.), and triethylamine (1.3 equiv.). Purification by column chromatography (MeOH/DCM (5:95)) gave the title compound as colorless oil. 1H-NMR (300 MHz, CDCl3): δ 8.50 (d, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 4.50 (d, 2H), 4.20 (q, 2H), 3.05 (m, 2H), 2.01 (s, 6H), 1.50-1.05 (m, 20H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[CH3:31]O>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CO
Agent: Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A mixture of 100 g cholic acid, 300 ml of methanol and 10 ml concentrated hydrochloric acid was refluxed on steam for 20 minutes. The resulting brown solution was refrigerated to induce crystallization. The crystals were collected, washed with 50 ml cold methanol, and dried to give 103 g methyl cholate, m.p. 153-154° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.C1(CCCNC(C2N=NC(Cl)=CC=2)=O)CC1.[F:32][C:33]1([F:49])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[C:34]1=[O:48]>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:45]3[CH2:46][CH2:47][CH:42]([N:35]4[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]([F:32])([F:49])[C:34]4=[O:48])[CH2:43][CH2:44]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: O=C(NCCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(N3C(=O)C(F)(F)c4ccccc43)CC2)nn1
Yield: 77 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to replace 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide to react with 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one, the title compound was obtained as a white powder in 77% yield (0.075 g). 1H NMR (300 MHz, CDCl3) δ 8.06 (m, 2H), 7.56-7.53 (m, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.21-7.04 (m, 2H), 6.88 (d, J=6.9 Hz, 1H), 4.73-4.69 (m, 2H), 4.46-4.35 (m, 1H), 3.61-3.52 (m, 2H), 3.17-3.09 (m, 2H), 2.50-2.37 (m, 2H), 1.97-1.93 (m, 2H), 1.59-1.43 (m, 2H), 0.81-0.68 (m, 1H), 0.51-40 (m, 2H), 0.11-0.06 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 165.2, 163.0, 159.6, 145.0, 142.4, 142.3, 133.5, 127.2, 125.2, 123.8, 120.4, 112.6, 110.8, 110.3, 50.9, 44.7, 39.7, 34.5, 27.6, 8.7, 4.2. MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:40][N:6]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1COCCN1C(=O)N(N)c1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 28.8 %

Procedure:
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3): 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: Oc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) were dissolved in dichloromethane (1000 ml), the solution was cooled in an ice bath and triethylamine (219 ml) was added portionwise such that the reaction temperature was kept below 20° C. Propionyl chloride (137 ml) was then added over 1 hour and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water followed by brine, then dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 4-bromophenyl propionate (344 g) as a green oil.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=2[CH2:10][CH2:11][N:12]([CH2:22]OC(=O)C2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]3[CH:35]=[CH:34][CH:33]=[CH:32][C:9]=3[CH2:10][CH2:11][N:12]([CH2:22][C:2]3[CH:37]=[CH:36][C:55]([C:54]([O:57][CH3:58])=[O:56])=[CH:4][CH:3]=3)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:36][CH:37]=2)=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(Br)cc1)COC(=O)c1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(-c2ccc(Cl)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
300.0 mg (0.51 mmol) of methyl 4-({[{2-[(4-bromobenzyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 4 are initially charged in 3 ml of dimethoxyethane and admixed successively with 101.7 mg (0.62 mmol) of 4-chlorophenylboronic acid and 0.57 ml of 2M sodium carbonate solution. 10.0 mg of dichlorobis(triphenylphosphine)palladium(II) are added, and the mixture is then heated at reflux temperature for 18 hours. The reaction solution is cooled, admixed with 20 ml of ethyl acetate and washed successively with 5% strength sodium hydrogen phosphate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off under reduced pressure. The crude product is chromatographed over silica gel using the mobile phase cyclohexane/ethyl acetate=10:1.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH:9]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]([NH:27][C:28]4[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[CH:23]=[C:24]([CH3:26])[CH:25]=3)[CH:17]=[N:16]2)CCC[CH:11]=[CH:10]1.[CH3:38][C:39]([CH3:41])=[O:40]>O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[CH3:26][C:24]1[CH:25]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH:9]3[CH2:10][CH2:11][CH2:41][CH:39]([OH:40])[CH:38]3[OH:5])[CH:19]=2)[CH:21]=[C:22]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3C=CCCC3)c2)c1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCCC(O)C3O)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Osmium tetroxide (2.08 mL, 0.34 mmol) and 4-methylmorpholine N-oxide (398 mg, 3.4 mmol) were added to a flask containing racemic N-{3-[1-(cyclohex-2-en-1-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (339 mg, 0.85 mmol) dissolved in acetone (7.5 mL) and water (0.94 mL). The suspension was stirred for 2.5 hours at room temperature. The mixture was diluted with saturated aqueous sodium thiosulfate and stirred for 15 minutes at room temperature. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford racemic 3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexane-1,2-diol. MS ESI calcd. for C21H23F3N5O2 [M+H]+ 434. found 434.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:66]([CH3:68])[CH3:67])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:66]([CH3:68])[CH3:67])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in ether (6 ml) is added boron trifluoride etherate (10 μl) followed by freshly prepared 2-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd. aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound and its 4"-isomer.
Reaction SMILES: C(O)C(O)C.[Na].[CH3:7][C@H:8]([C:21]([OH:23])=[O:22])[C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][C:17]=2[CH:18]=1.[O-]CC.[Na+:27].C(O)C>C(OCC)C>[CH3:7][C@H:8]([C:21]([O-:23])=[O:22])[C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][C:17]=2[CH:18]=1.[Na+:27]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(O)CO
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Reaction time: 0.02 h

Procedure:
A propylene glycol solvate of a sodium salt of naproxen was prepared. To a solution of naproxen (348 mg, 1.51 mmol) in diethyl ether (10 mL) was added propylene glycol (0.200 ml, 2.72 mmol). To the clear solution was added sodium ethoxide in ethanol (21%, 0.750 mL, 2.01 mmol). The solution became slightly yellow due to the sodium ethoxide. After 1 minute, crystals began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with diethyl ether (10 mL). The product was then air-dried and collected. The solvate was 2:1 naproxen Na:propylene glycol. The solid was characterized by TGA and PXRD.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4]C=1O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.F[C:29](F)(F)S([O-])(=O)=O.[CH:36](OC)(OC)[O:37][CH3:38]>CCO>[Br:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:36]([CH3:29])[O:37][C:38]=2[CH:4]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(OC)OC
Reactant: Nc1cc(Cl)c(Br)cc1O
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2cc(Cl)c(Br)cc2o1
Temperature: 90 °C
Yield: 90.3 %

Procedure:
A mixture of 2-amino-5-bromo-4-chlorophenol (53) (4.746 g, 21.1 mmol), trifluoromethanesulfonic acid Ytterbium (III) salt (130 mg, 1% mol) and trimethyl orthoformate (4.03 ml, 1.5 eq.) in 15 ml EtOH was heated at 90° C. for 1 h. After cooling down to r.t. Crystalline formed was filtered, washed with MeOH, dried to give 4.694 g 54 as pale brown fine needles (yield: 90.3%)
Reaction SMILES: [I-].C(OC([NH:9][C:10]([CH3:20])([CH3:19])[CH2:11][N+:12]1([CH3:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=O)(C)(C)C.[ClH:21]>CO.O1CCOCC1>[Cl-:21].[NH2:9][C:10]([CH3:20])([CH3:19])[CH2:11][N+:12]1([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cl
Reactant: CC(C)(C[N+]1(C)CCOCC1)NC(=O)OC(C)(C)C
Agent: [I-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(N)C[N+]1(C)CCOCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
4-(2-(tert-Butoxycarbonylamino)-2-methylpropyl)-4-methylmorpholin-4-ium iodide (840 mg, 2.1 mmol) was dissolved in methanol (5 ml). To the solution was added 4M hydrogen chloride in dioxane (25 ml), and stirred for 4 hours at room temperature. The reaction mixture was concentrated and dissolved in water. Silver oxide (1.0 g) was added to the aqueous solution and the mixture was stirred at room temperature for 30 minutes. The solution was filtered through Celite®, and concentrated hydrochloric acid (0.5 ml) was added to the solution. The solution was filtered through Celite® a second time, and the aqueous solution was concentrated in vacuo to give 380 mg (87%) of 4-(2-amino-2-methylpropyl)-4-methylmorpholin-4-ium chloride. MS (ESI+) calculated for C9H21N2O+: 173.16, Found: 173 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:31][CH2:32][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCNCC1
Reactant: ClCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(=O)N1CCN(CCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-3-[2-(4-Acetylpiperazin-1-yl)ethyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and 1-acetylpiperazine following General Procedure G.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12](Cl)(Cl)=[O:13].C(N(CC)CC)C.[CH3:23][N:24]([CH3:40])[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=1[S:35]([NH2:38])(=[O:37])=[O:36].[OH-].[K+]>C(OCC)(=O)C>[CH3:23][N:24]([CH3:40])[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=1[S:35]([NH:38][C:12]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:13])(=[O:36])=[O:37]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc([N+](=O)[O-])ccc2C(=O)N(C)C)n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ethyl acetate (16 ml) and 2-amino-4,6-dimethoxypyrimidine (5.0 g, 32.2 mmol) were introduced and cooled to −10° C. under nitrogen. Phosgene (5.1 g, 51.5 mmol) was passed in at this temperature and a solution of triethylamine (6.5 g, 64.2 mmol) in ethyl acetate (20 ml) was added dropwise in the course of 1 hour. After 1 hour, the reaction was warmed to 20° C. and nitrogen was blown through until it no longer contained phosgene, and then N,N-dimethyl-2-aminosulfonyl-4-nitrobenzamide (8.1 g, 29.6 mmol) was added. The mixture was cooled to −10° C. and a solution of triethylamine (3.3 g, 32.7 mmol) in ethyl acetate (15 ml) was added dropwise in the course of 60 minutes, and the mixture was stirred for 30 minutes and warmed to room temperature. Potassium hydroxide solution (1.0M, 100 ml) was then added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The aqueous phase was adjusted to pH=2 using 6M hydrochloric acid, and the product was filtered off, washed with water (2×20 ml) and dried. Yield: 10.28 g, 72.6% of theory.