Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1([CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:25][O:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]([OH:24])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH2:25][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][NH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 47 %

Procedure:
5-Nitroindazole (3.44 g, 21.08 mmol) was suspended in N,N-dimethylformamide (100 ml) and sodium hydride (0.93 g, 23.19 mmol) was slowly added to the suspension at 0° C., followed by stirring for 30 min and then for an additional 30 min at room temperature. The addition of 1-((2-(2,4-difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (5 g, 21.08 mmol) was performed before stirring at 60° C. for 2 hours. The addition of water (1 ml) at 0° C. led to termination of the reaction. After being diluted with ethyl acetate (200 ml), the reaction mixture was washed with saturated ammonium chloride solution (200 ml) and then with brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and vacuum evaporated to concentrate it. The product was purified by chromatography on silica gel to give the title compound (Yield 47%). This compound was found to have a melting point from 63 to 64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cn[nH]c1-c1cc(C(=O)N2CC(c3ccc(C#N)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC.HCl (99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and the solution was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35.0% CH3CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0% in 2 min); Detector, UV 254 & 220 nm. The fractions contained pure product were combined and lyophilized to obtain the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[NH:10][C:3]=12.O=P(Cl)(Cl)[Cl:19]>C(#N)C>[CH2:15]([O:14][C:12]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:19])=[C:3]2[NH:10][C:9]=1[CH3:11])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1c(C)[nH]c2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12

Procedure:
Ethyl 7-hydroxy-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (44.0 g, 0.20 mol) is suspended in dry acetonitrile (400 mL). After addition of POCl3 (47 mL, 0.50 mol) the stirred reaction mixture is heated to reflux for 4 hours. The volatiles are removed under reduced pressure. The residue is suspended in ice-cold water (500 mL) and carefully neutralized to pH 8 by dropwise addition of 6N NaOH. Stirring is continued at ambient temperature over night. The pH is readjusted to 8, the product is filtered, washed with several small portions of water and dried in vacuum at 50° C. for 24 hours to yield the title compound as off-white solid.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.[CH3:44][O:45][C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1>O1CCOCC1.C(OCC)(=O)C.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>[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[CH:51]=2)=[CH:11][N:10]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CC(F)(F)F)cc(-c5ccc(F)cc5)c4=O)cc3)c2)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 10 %

Procedure:
Water (0.1 ml), potassium carbonate (70 mg) and tetrakis(triphenylphosphine)palladium (19 mg) were added to a solution of the compound obtained in Step 1 of Example 31 (95 mg) and 3-methoxyphenylboronic acid (31 mg) in 1,4-dioxane (1.5 ml), and the mixture was stirred at 90° C. for 17 hours. After leaving to cool, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:methanol=300:1->100:1 (v/v)] to give 10 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1.O>C1COCC1>[I:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(I)c(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Methyl-2-iodobenzoic acid (100 g, 0.38 mol) is dissolved in THF (350 ml) and cooled in an ice bath. Borane-THF complex (380 ml of 1M in THF, 0.38 mol) is added dropwise. After addition is complete, the reaction is warmed to room temperature and stirred for 14 hours. The mixture is transferred to a large erienmeyer flask, cooled in an ice bath, and carefully quenched with water (250 ml). Evaporation of the THF on a rotovap gives a white suspension which is treated with additional water (1 L) and then filtered and dried in a vacuum dessicator over P2O5 to give 2-iodo-5-methylbenzyl alcohol as a white solid, m.p. 82-85°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1C(O)=O.C([N:18](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)(C)(C)C.ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1[NH2:18]
Reactant: CCN(CC)CC
Reactant: COc1cc(OC)c(Cl)c(C(=O)O)c1F
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(N)c1F
Temperature: 82 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A suspension of 2-chloro-6-fluoro-3,5-dimethoxybenzoic acid (10.8 g, 0.0077 mol) and triethyl amine (0.934 g, 0.0092 mol) in tert-BuOH (50 mL) was stirred for 5 min. To the resulting reaction mixture, Diphenyl phosphoryl azide (2.53 g, 0.0092 mol) was added and heated up to 82° C. and kept at this temperature for overnight. The reaction mixture was then concentrated in vacuo to obtain a crude residue. The crude residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. TFA (4 mL) was added to the reaction mixture and the resultant reaction mixture was then stirred at room temperature for 2 h. The solvents were removed under vacuum and the crude residue was diluted with ethyl acetate and saturated sodium carbonate solution. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using the eluent (gradient hexane to hexane-ether (65:35)) to afford the title compound (0.95 g, yield: 60%) as solid. MS (ESI): 205.7 [M+H]+.
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49]([N:5]2[CH2:6][CH2:7][CH2:8][N:2]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[N:19]=[C:20]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[O:21][C:22]=4[C:23]([F:26])([F:24])[F:25])=[O:17])=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCCN(C(=O)[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (100 mg, 0.21 mmol), cis-cyclohexane-1,4-dicarboxylic acid monobenzyl ester (0.67 mg, 0.25 mmol), and triethyl amine (0.070 mL) in DMF (5 mL) was stirred for 5 minutes and PyBroP (116 mg, 0.25 mmol) was added. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. The residue was extracted with ethyl acetate and washed with saturated ammonium chloride (100 mL), water (50 mL), brine (100 mL) and dried with anhydrous sodium sulfate. The solvent was removed and the crude material was purified on a flash column chromatography eluted with ethyl acetate/hexanes to afford cis-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (100 mg, 71% yield) as a white solid. LCMS for C37H37F3N4O5 calcd. (m/e) 674, observed 675 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:30]([O:29][C:27]([C:26]1[C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:28])[CH3:31]
Reactant: N#Cc1c(N)cccc1CCC1CCCCC1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile (Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H), 1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m, 2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q, J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63 (brs, 2H). MS 413 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].C(O)(=O)C.[C:40](=[O:45])([O:43]C)[O:41][CH3:42]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][C@H:13]3[O:45][C:40]([O:41][CH3:42])=[O:43])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@H]1C[C@H](OC(C)=O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Reactant: COC(=O)OC
Solvent: CC(=O)O
Product: COCO[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregn-6-en-5α-ol, following by addition of 0.2 ml of acetic acid. The mixture was stirred in an atmosphere of argon gas at a temperature of 100° C. for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 130 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].C[O:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>C(Cl)Cl>[CH2:5]([NH:7][C:8](=[O:9])[O-:10])[CH3:6].[OH:12][C:13]1[C:14]([Cl:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Product: CC1c2cc(Cl)c(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BBr3 (3.7 mL, 1.0 M in CH2Cl2) was added to a solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (0.49 g, 1.6 mmol) in CH2Cl2 (32 mL), and stirred overnight at room temperature. The excess BBr3 was quenched with the dropwise addition of H2O (10 mL), and washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic extract was dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C15H18ClNO3+H: 296, observed: 296.
Reaction SMILES: C[Si](I)(C)C.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[CH:25][CH:24]=2)[NH:19][N:18]=[C:17]3[NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[CH:10][CH:9]=1)[CH3:7]>CO>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[NH:19][N:18]=[C:17]3[NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(CC)cc3)cc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)c(-c3ccc(CC)cc3)cc12
Yield: 36.8 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 600 mg of N-[5-(4-ethylphenyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, and the mixture is refluxed for 18 hours. 30 cm3 of methanol are added and the reaction medium is refluxed for 5 minutes and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with 2×100 cm3 of 10% sodium thiosulphate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure to give 650 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 15 cm3 of diisopropyl ether, filtered off, washed with 5 cm3 of ethyl acetate and then with 10 cm3 of diisopropyl ether, and dried (90 Pa; 45° C.) to give 180 mg of N-[5-(4-ethylphenyl)-6-(4-hydroxyphenyl)-1H-indazol-3-yl]-butanamide in the form of cream-coloured crystals melting at 225° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(OCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(OCCCI)cc1
Yield: 96.7 %

Procedure:
A solution of N-[4-(3-chloro-1-propyloxy)phenyl]methanesulfonamide (1.03 g, 3.90 mmol) and sodium iodide (1.75 g, 11.70 mmol) in acetone (15 mL) was heated under reflux for 18 hours. The mixture was concentrated, taken up in EtOAc, and washed with brine, 10% aqueous sodium bisulfite, and brine. The organic phase was dried (MgSO4) and concentrated to give 1.34 g (96%) of product as an off-white solid m.p. 109°-111° C.
Reaction SMILES: C(OC([NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:14])[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)(Cl)Cl.[C].[Pd]>[NH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CC(=O)NCc1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)(C)N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of N-(4-(1-benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide (9.57 g) in methanol (200 ml) and chloroform (200 ml) was added 10% palladium-carbon (5.0 g) and the mixture was stirred for 5 hr while introducing a hydrogen gas. The reaction mixture was passed through Celite and the solvent was evaporated to give the title compound (5.8 g) as a pale-yellow amorphous solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[O:14]=[C:15]1[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]1>C(#N)C.O>[Si:1]([O:14][C:15]1[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1=NNC(=O)C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Tert-butyldimethylsilyl chloride (6.05 g, 40.15 mmol) and imidazole (2.92 g, 42.82 mmol) were added to a stirred solution of ethyl 5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate (4.18 g, 26.76 mmol) in ACN (90 mL). The mixture was stirred at room temperature for 30 minutes, then diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-3-carboxylate (3.2 g, 44% yield) as a yellow solid, that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]([NH:18]C(=O)C)=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]([NH2:18])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1OCN1CCC(C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(N)cc1OCN1CCC(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.8 %

Procedure:
To a solution of N-[4-methoxy-5-(4-methyl-piperidin-1-ylmethoxy)-2-nitro-phenyl]-acetamide (1.34 g, 3.97 mmol) in MeOH (40 ml) was added sodium methoxide (1 g, 18.5 mmol) reaction stirred RT for 48 hours then reduced in vacuo. The residue was triturated with water and the solid filtered and washed with further water. Solid dried to yield 4-Methoxy-5-(4-methyl-piperidin-1-ylmethoxy)-2-nitro-phenylamine (0.9 g), (LC/MS (acidic method): Rt 1.72, [M+H]+ 296)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+]>CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[CH2:30])[OH:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=C(O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Yield: 106.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 0.0195 mol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g, 0.0195 mol), KI (200 mg), NaHCO3 (1.8 g, 0.0215 mol) and CH3CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%) of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzene methanol as a light beige solid, m.p.=142°-144° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21](N)=[NH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=C1C(=O)CCCC1=O)C>CCO>[C:14]([Si:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:18][CH2:19][CH2:20][C:21]#[N:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Agent: CN(C)C=C1C(=O)CCCC1=O
Solvent: CCO
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A Solution of 3-(tert-butyldiphenylsilyloxy) propanamidine (25 g, 77 mmol) and 2-((dimethylamino)methylene)cyclohexane-1,3-dione (12.8 g, 77 mmol) in 400 mL of dry EtOH was heated at 80° C. for 3 h. After cooling to room temperature, the solvent was evaporated. Flash chromatography (SiO2, EtOAc/hexane=1:1) gave the title compound as a white solid.