Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[CH:43]1([NH:46][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:12]=[C:11]4[C:23]3[N:28]=[C:27]([O:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:31]4)[CH:26]=[N:25][CH:24]=3)[CH:5]=[CH:4][N:3]=2)[CH2:45][CH2:44]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(Cl)n5)cc34)n2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(NC6CC6)n5)cc34)n2)C1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
A mixture of (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (172 mg, 0.290 mmol), cyclopropylamine (0.12 mL, 1.74 mmol) and DIPEA (0.25 mL, 1.45 mmol) in THF (1.5 mL) was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min and heated at 140° C. for an additional 1 h. 1 M HCl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(2-(cyclopropylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (116 mg, 0.19 mmol, 65% yield) as a clear oil. MS (ESI, pos. ion) m/z: 613.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([F:25])[CH:17]=1.[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([F:25])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.42 g) described in Preparation Example 47 was dissolve in tetrahydrofuran (32 mL), 4-bromo-2-fluorobenzoyl chloride (3.0 g) and 1N aqueous sodium hydroxide solution (15 mL) were added, and the mixture was stirred at room temperature. The reaction mixture poured into water under cooling, 4N aqueous sodium hydroxide solution and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with 4N aqueous sodium hydroxide solution and saturated brine, then washed with saturated brine, sodium sulfate was added and dried. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (4.39 g).
Reaction SMILES: CN(C)[C:3](=[O:23])[CH2:4][C:5]1[N:12]2[C:8]([S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[N:7][C:6]=1[C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C[O:26]CCO.[OH-].[Na+]>O>[CH3:22][C:19]1[S:18][C:17]([C:6]2[N:7]=[C:8]3[N:12]([C:5]=2[CH2:4][C:3]([OH:23])=[O:26])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[S:9]3)=[CH:21][CH:20]=1
Reactant: COCCO
Reactant: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)O)s1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
23.8 g (0.067 mole) of N,N-dimethyl-2-(5-methylthien-2-yl) imidazo[2,1-b]benzothiazole-3-acetamide and 450 ml of 2-methoxyethanol are introduced into a 1 liter round-bottomed flask, and the mixture is stirred and it is heated on an oil bath at around 130° C. until the solid dissolves. A solution of 13.4 g (0.335 mole) of sodium hydroxide pellets in 70 ml of water is added hot, with precaution, then after 30 minutes, a further 13.4 g (0.335 mole) of sodium hydroxide pellets in 70 ml of water, and the heating is maintained for 7 h 30 min, while monitoring the progress of the reaction by thin-layer chromatography. The mixture is cooled to around 20° C., the solvent is evaporated under reduced pressure, without exceeding 60° C. 1200 ml of water are added to the residue, an insoluble matter is removed by filtration, 150 ml of acetic acid are added to the filtrate up to a pH=4. A yellow-coloured precipitate is obtained which is stirred for 30 minutes while cooling to around 5° C. The solid is separated by filtration, it is washed with water and then with diethyl ether, and it is dried under vacuum at around 60° C. 17.5 g of compound are obtained of which 1.65 g (0.005 mole) are purified by recrystallization from 250 ml of boiling methanol. 1.1.g of a light yellow-coloured solid are isolated. Melting point: 255°-259° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([O:11][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCOC(=O)C1CCC(O)C1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A solution of 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (prepared as described in PCT Int. Appl. 2008131946, 3.180 g, 20.1 mmol) in dichloromethane (100 mL) was subsequently treated with 2,6-lutidine (4.7 mL, 40.2 mmol) and triisopropylsilyl trifluoromethanesulfonate (8.1 mL, 30.15 mmol). After stirring for 3.5 h, the reaction was quenched with pH 4 buffer. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (6.15 g, 97%) as a light yellow oil and as a 3.5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3): δ 1.04-1.08 (m, 27H), 1.27 (t, J=7.1 Hz, 4H), 1.70-2.00 (m, 5.2H), 2.04-2.21 (m, 2.6H), 2.66-2.79 (m, 1H), 2.97-3.10 (m, 0.3H), 4.14 (q, J=7.1 Hz, 2.6H), 4.29-4.39 (m, 1H), 4.43-4.50 (m, 0.3H).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:70](OC)[O:71]C)[CH2:67][C:68]#[CH:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C.ClCCl.O>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][C:68]#[CH:69])[CH:70]=[O:71])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C#CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C#CCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Yield: 64.8 %

Procedure:
70 mg (0.067 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide were stirred in a mixture of 4 ml of trifluoroacetic acid, 4 ml of dichloromethane and 30 mg of water at room temperature for 30 minutes. The solution was evaporated to dryness in a vacuum and the residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (60:13:2:2) for the elution. There were obtained 36 mg of 2(RS)-[[N-[N-[N-[N-[N-[(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentynal (9:1 mixture of diastereoisomers) as a white solid. MS: m/e 829.6 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:12]([O:11][C:5]1[CH:4]=[C:3]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:2]([Br:1])=[CH:10][C:6]=1[C:7]([NH:44][C:43]1[CH:45]=[CH:46][CH:47]=[C:41]([Cl:40])[CH:42]=1)=[O:8])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-Bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in D7) (1 g, 2.461 mmol) in N,N-Dimethylformamide (DMF) (20 mL) was added EDC (0.849 g, 4.43 mmol), 1-hydroxy-7-azabenzotriazole (0.503 g, 3.69 mmol), 3-chloroaniline (0.504 mL, 4.92 mmol), DIPEA (0.860 mL, 4.92 mmol) and the mixture was stirred at room temperature overnight. The DMF was removed on a buchi under reduced pressure, the residue was taken up into DCM (50 ml) and washed with water (2×20 ml). The DCM was evaporated on a buchi under reduced pressure and the residue was purified using the Companion eluting with 0-50% ethyl acetate/cyclohexane to give the title compound as pale yellow oil which solidified on standing. Yield: 400 mg
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.N1CCCCC1>CCO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH:19]=[CH:17][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=2)=[O:18])[CH:21]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)C=Cc2cccnc2)c1

Procedure:
A mixture of 16 (4.0 g, 16 mmol), nicotinaldehyde (1.89 mL, 20 mmol), and piperidine (4.0 mL, 40 mmol) in absolute EtOH (65 mL) was heated at reflux for 16 h. The mixture was cooled and concentrated in vacuo. Chromatography on silica gel (30-60% EtOAc/hexanes) gave a mixture of unreacted nicotinaldehyde and 17 (both have the same Rf on TLC). Washing of the mixture with hexane in a filter funnel provide 1.73 g (32%) of pure 17 as a yellow crystal. 1H NMR (CDCl3, 300 MHz) 8.87 (d, J=2.1 Hz, 1H), 8.66 (dd, J=4.8, 1.5 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.80 (d, J=16.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.60 (d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.20 (dd, J=8.2, 2.6 Hz, 1H), 4.62 (s, 2H), 1.52 (s, 9H); 13C NMR (CDCl3, 75 MHz) 189.7, 175.0, 168.0, 158.7, 151.6, 150.5, 141.4, 139.5, 134.9, 131.0, 130.2, 124.2, 122.3, 120.6, 114.1, 83.1, 66.2, 28.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.O.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:13]1[NH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (1.0 g, 0.0027 mol) in fuming nitric acid (95%, 1 ml) and fuming sulphuric acid (30% free SO3, 1 ml) was stirred and heated at 120° C. for 3.5 hours. The mixture was poured into cold water (50 ml) and the solid was filtered off and washed with water. The resultant solid was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and n-hexane (1:5) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro 4-trifluoromethylimidazole (0.7 g) as an off-white solid, m.p. 244°-252° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.Cl[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(F)cc(Br)cc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(F)cc(Br)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
907 mg of 5-bromo-3-fluoro-2-methoxybenzyl alcohol was dissolved in 10 ml of N,N-dimethylformamide. 400 mg of imidazole and 1.06 g of chloro(t-butyl)diphenylsilane were added, followed by stirring for 1 hour at room temperature and for 0.5 hours at 50° C. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, to give 1.882 g of [(5-bromo-3-fluoro-2methoxybenzyl)oxy](t-butyl)diphenylsilane.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[C:30]([F:34])[CH:31]=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]=1[C:35]#[N:36]
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(F)c3C#N)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1c(F)cccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 3,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 7.31 (2H, dd, J 7 and 3), 7.43-7.49 (2H, m), 7.64-7.75 (3H, m), 8.10 (1H, s), 9.04 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:37]4[CH2:38][CH2:39][CH:34]([CH2:33][OH:32])[CH2:35][CH2:36]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OCC1CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OCC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 4-hydroxymethylpiperidine (55.9 mg; 0.48 mmol) to give Example 139 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.48, 1.64 Hz), 7.97-7.86 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.55-7.48 (4H, m), 4.43 (1H, t, J=5.3 Hz), 3.55 (2H, s), 3.28 (2H, t, J=5.8 Hz), 2.84 (2H, d, J=10.8 Hz), 1.96 (2H, t, J=11.3 Hz), 1.66 (2H, d, J=12.6 Hz), 1.37 (1H, d, J=10.8 Hz), 1.25-1.12 (2H, m). LC/MS (Method C): 512 (M+H)+. HPLC (Method E) Rt 2.16 min (Purity: 99.2%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH:3]([O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(CC(O)CBr)OCC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CC(CBr)OC1CCCCO1)OCC
Yield: 128.1 %

Procedure:
(1)-(b) To a mixture of diethyl 3-bromo-2-hydroxypropylphosphonate (82.5 g) and p-toluenesulfonic acid (1.03 g) was added dropwise 3,4-dihydro-2H-pyrane (250 g) under ice-cooling and with stirring. After the reaction mixture was stirred at the same temperature for 10 minutes and at ambient temperature for 1.5 hours. The dihydropyrane was removed off by evaporation under reduced pressure to give a residue, which was dissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (100 ml) and with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily diethyl 3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (138 g).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]([CH:34]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:35]OS(C)(=O)=O)=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:35][CH:34]([C:33]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:26]=[C:27]3[C:32]=2[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 4-mercaptobenzoate (54.0 mg, 0.306 mmol; CAS Reg. No. 6302-65-4) in dry DMF (3 ml) was added K2CO3 (43.0 mg, 0.306 mmol) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. [rac]-Methanesulfonic acid 2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethyl ester (135.0 mg, 0.306 mmol) dissolved in dry DMF (1 ml) was then added at 0° C. The reaction mixture was then heated at 100° C. in a sealed tube for 12 hours. LC-MS shows the formation of the desired compound with some starting material. 10 ml of 10% citric acid solution was then added to the reaction mixture and extracted with EtOAc (3×8 ml). Combined organic layers were washed with brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get light yellow oil (234 mg), which was purified by column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 8/92] to give the title compound (57 mg, 36.2%) as a off white sticky solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[O-:18][Mn](=O)(=O)=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:18])=[O:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60° C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37% (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83% yield). This product was used without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:21]([O-])=O)=[C:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:21][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([OH:1])[CH:3]=2)=[CH:11][C:10]=1[N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1N
Yield: 83.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(3-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (7.8 g), palladium on carbon (10%, 0.9 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (6 g).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([O:11][CH:12]([CH3:22])[CH2:13][N:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][Br:26]>ClCCCl>[Br-:26].[C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([O:11][CH:12]([CH3:22])[CH2:13][N+:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)([CH3:25])[CH3:15])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(CN(C)C1CCCCC1)OC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CBr
Solvent: ClCCCl
Product: CC(C[N+](C)(C)C1CCCCC1)OC(=O)c1ccc(C(C)(C)C)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexyl(methyl)amino)propan-2-yl 4-(tert-butyl)benzoate (22.5 g, 67.98 mmol) in DCE (150 ml) was added methyl bromide (25% solution in toluene, 103 ml, 271.90 mmol) and reaction mixture was stirred at rt for 16 h. TLC showed very small amount of unreacted starting material. Hence another 0.5 eq. of methyl bromide was added and stirred at rt for 8 h. The reaction mixture was concentrated and the crude material was purified by chromatography on neutral alumina eluting with 2-8% methanol-DCM to provide an off white solid. The solid material was crystallized from DCM-ether to provide [2-(4-tert-butyl-benzoyloxy)-propyl]-cyclohexyl-dimethyl-ammonium bromide. Yield: 15.5 g (53.5%). 1H NMR (DMSO-d6) δ 7.94 (d, J=8 Hz, 2 H), 7.57 (d, J=8 Hz, 2 H), 5.54-5.51 (m, 1 H), 3.93 (dd, J=15, 9 Hz, 1 H), 3.63 (d, J=14 Hz, 1 H), 3.42-3.36 (m, 1 H), 3.05 (s, 6 H), 2.23-2.20 (m, 1 H), 2.11-2.08 (m, 1 H), 1.87-1.83 (m, 2 H), 1.57-1.43 (m, 3 H), 1.36 (d, J=6 Hz, 3 H), 1.30 (s, 9 H), 1.23-1.08 (m, 3 H); LCMS: m/z=346.4 [M+], RT=3.00 min, (Column: Y, Program: P1). UPLC: 99.90% (200 nm), RT=4.04 min (Mobile Phase A. 0.05% TFA in water, B. Acetonitrile; Column: Zorbax® SB-C18 (4.6×50 mm) 1.8μ).