Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:24]([F:27])([F:26])[F:25])[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:23])[O:11]2)=[O:7])=[CH:4][CH:3]=1.C1N=C[N:32](C(N2C=NC=C2)=O)[CH:31]=1.CN>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:24]([F:26])([F:25])[F:27])[C:15]3[CH:16]=[C:17]([C:20]([NH:32][CH3:31])=[O:22])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:23])[O:11]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccc(C(=O)O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)C(CNC(=O)c1ccc(F)cc1)(C(F)(F)F)OC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Fluorobenzoyl)amino]methyl}-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid (30 mg, 0.073 mmol) and CDI (23.6 mg, 0.15 mmol) were dissolved in THF (230 μL) and DMF (90 μL), and the solution was stirred at room temperature for 30 minutes and thereafter, methylamine (182 μL, 0.36 mmol) was added thereto. The reaction solution was stirred at room temperature for 30 minutes and then diluted with ethyl acetate, which was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, whereby the objective compound (10.2 mg, 33%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][C:7]=1[NH2:18].[N:19]#[C:20][Br:21]>CC(O)C>[BrH:21].[N:12]1([C:9]2[CH:10]=[CH:11][C:6]3[C:2]4[N:1]([CH2:5][CH2:4][N:3]=4)[C:20]([NH2:19])=[N:18][C:7]=3[CH:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1cc(N2CCOCC2)ccc1C1=NCCN1
Reactant: N#CBr
Solvent: CC(C)O
Product: Br
Product: NC1=Nc2cc(N3CCOCC3)ccc2C2=NCCN12
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a suspension of [2-(4,5-dihydro-1H-imidazol-2-yl)-5-(morpholin-4-yl)phenyl]amine 3.60 g (14.6 mmol) in 2-propanol 20 mL was added cyanogen bromide 2.32 g (21.9mmol) portionwise at 0° C. and stirred at 100° C. for 2 hours. After cooling to room temperature, the precipitate was collected and washed with diethyl ether to give the title compound 1.20 g as yellow solid. Yield 77.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Cl.Cl[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:26][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: ClCc1cscn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cscn3)c3ccccc3c2=O)cc1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Compound 4j was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 50 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one 3a, 19 mg (0.47 mmol) of 60% sodium hydride and 40 mg (0.25 mmol) of 4-chloromethyl thiazole hydrochloride were combined in 1 mL N,N-dimethylformamide and stirred at 70° C. for 2 h. The crude product was purified by flash chromatography using 20-100% ethyl acetate in hexane yielded 54 mg of the product as white solid: LC-MSD, m/z for C22H18N2O2S [M+H]+=375.5; HPLC retention time: 2.1 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 7.1-7.2 (m, 2H), 7.4-7.5 (m, 1H), 7.5-7.6 (m, 2H), 7.6-7.7 (m, 2H), 8.3 (s, 1H), 8.45-8.5 (m, 1H), 8.8-8.85 (m, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[N:10]=[C:11](N)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl.C([CH2:17][O:18][C:19]1[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=1)#N>O.COCCO.CCO>[Cl:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:17][O:18][C:19]3[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: COCCO
Product: NC(=O)c1c(F)ccc(OCc2nc3c(Cl)cccc3s2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(Method K) A solution of KOH (15.15 g, 270 mmol, 20 equiv.) in H2O (25 ml) was added to a solution of 4-chloro-1,3-benzothiazol-2-amine (2.5 g, 13.5 mmol, 1 equiv.) in 2-methoxy-ethanol (25 ml) and the reaction mixture was heated under reflux overnight. After cooling at r.t., the mixture was diluted with H2O (200 ml), acidified with 5N HCl solution to pH 4 and extracted with CH2Cl2 (3×150 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure to dryness, to give 1.5 g (70% yield). From this crude residue, 167 mg (assuming 1.05 mmol), were mixed with 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide (150 mg, 0.7 mmol) and the mixture was stirred at 120° C., in a pre-heated oil bath, under N2, for 2 h. EtOH (2 ml) was added and the reaction mixture was heated for a further 2 h. After cooling at r.t., the solid was filtered, washed with EtOH and re-crystallised from EtOAc/pentane, to give the desired product as a pale yellow solid, 62 mg (25% yield on second step). HPLC-MS (method 1): m/z 355 [M+H]+, Rt=3.75 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:12][CH2:11][C:10](=[O:13])[NH:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][Br:25])=[O:23])=[CH:18][CH:17]=1>C(O)C>[Br-:25].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][N+:1]2[CH:2]=[CH:3][C:4]([C:7]3[NH:12][CH2:11][C:10](=[O:13])[NH:9][N:8]=3)=[CH:5][CH:6]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C1CNC(c2ccncc2)=NN1
Solvent: CCO
Product: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CN3)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
4,5-Dihydro-3-(4-pyridyl)-1,2,4-triazin-6(1H)-one (176 mg, 1 mmol) and 4'-methoxyphenacyl bromide (252 mg, 1.1 mmol) were dissolved in absolute ethanol (5 ml), refluxed for two hours and then stirred at room temperature for one day. The resulting precipitate was collected by filtration and washed with absolute ethanol to obtain the titled compound (374 mg) as yellow-brown powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC.CON(C)[C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].Cl>O1CCCC1>[C:40]([C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7])(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C(O)c1ccoc1
Reactant: CON(C)C(=O)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(C)(C)C(=O)c1occc1C(=O)O
Temperature: -20 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
A solution of 3-furoic acid (8.97 g, 0.08 mol) in tetrahydrofuran (200 ml) was cooled to -70° C. and a 2.0M solution of lithium diisopropylamide in THF-ethylbenzene-heptane (80 ml, 0.16 mol) was added dropwise over 3/4 hr at -70° to -20° C. under nitrogen to give a tan suspension. A red solution formed after stirring for 113/4 hours at -20° C. To this solution was added N-methoxy-N-methylpivalamide (11.67 g, 0.08 mol) in tetrahydrofuran (10 ml) at -40° C. The reaction mixture was left at ambient temperature overnight. Then ,it was cooled in ice and neutralized with 6N ethanolic hydrogen chloride (50 ml). The neutralized solution was acidified with 1.5N HCl (150 ml) and was extracted with ether (300 ml). The ether extracts were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated in vacuo to a brown solid (15.4 g). Chromatography on silica gel using hexane-THF-acetic acid (10-2-0.2) gave a yellow solid (9.8 g), mp 85°-89° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[C:9](/[CH2:11]P(OCC)(OCC)=O)\[CH3:10])=[O:7].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[C:20]1(=[CH:11][C:9]([CH3:10])=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(C)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 1.8 g, 40 mmol) in DMF (60 mL) was added triethyl 3-methyl-4-phosphonocrotonate (11 g, 41.6 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added cyclohexanone (3.93 g, 40 mmol), and the mixture was stirred for 3 hours. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain oily crude resultant product of ethyl 4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of this compound in THF (160 mL) and methanol (40 mL) was added a 12 N aqueous sodium hydroxide solution (4.0 mL) at room temperature, and the mixture was stirred for 16 hours, and then was concentrated under reduced pressure. To the residue was added water and hydrochloric acid, and the mixture was acidified, which was extracted with ethyl acetate. The organic layer was washed with water, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude resultant product of 4-cyclohexylidene-3-methyl-2-butanoic acid. To a mixture of this compound (6.1 g, 33.8 mmol) in acetic acid (150 mL) was added sodium acetate (12 g, 33.8 mmol) at room temperature, and the mixture was heated under reflux under argon atmosphere for 24 hours. The solvent was concentrated under reduced pressure, water was added to the residue, which was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5.1 g (yield 63%) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:27][CH:26]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A solution of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.42 g) and 3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester (0.63 g) in 1,4-dioxane (20 mL) was added to polyphosphoric acid (3 g) at 100° C., and the resulting mixture was stirred at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate to afford title compound (0.39 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:12]([O:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=2)(=[O:24])=[O:23])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41](N(CCCC)CCCC)[CH2:42]CC.C(O)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:41]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:12]2[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:23])=[O:24])=[CH:26][C:27]=1[OH:34])[CH3:42]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(S(=O)(=O)Oc2c(-c3ccccc3)cc(C(=O)c3ccccc3)cc2-c2ccccc2)cc1O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A stirred solution containing 4-(5'-benzoyl-[1,1';3',1"]terphenyl-2'-yloxysulfonyl)-2-hydroxy-benzoic acid (0.106 g, 0.192 mmol), tributylamine (0.110 mL, 0.462 mmol), ethanol (0.0677 mL, 1.15 mmol) and 2-chloro-1-methyl pyridinium iodide (0.0607 g, 0.231 mmol) in CH2Cl2 (2 mL) was refluxed for 18 h. The reaction was cooled to ambient temperature, quenched with 1N HCl (20 mL) and extracted with EtOAc. The organic extracts were successively washed with 1N HCl (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.039g (35%) of the title compound as a white solid, mp 75-85° C. 1H NMR (DMSO-d6) δ 1.36 (t, 3H), 4.38 (q, 2H), 6.67 (d, 1H), 6.73 (dd, 1H), 7.30-7.36 (m, 6H), 7.45-7.52 (m, 5H), 7.57-7.61 (m, 2H), 7.68-7.71 (m, 3H), 7.84 (d, 2H), 10.60 (s, 1H). mass spectrum (El) m/z 578 (M+). Anal. Calcd. for C34H26O7S 0.5H2O: C,69.49; H,4.63; N,0.00. Found: C,69.38; H,4.76; N,0.10.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH3:100][N:101]1[CH:105]=[C:104]([CH2:106][NH2:107])[N:103]=[CH:102]1>>[ClH:45].[C:39]1([CH:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:107][CH2:106][C:104]4[N:103]=[CH:102][N:101]([CH3:100])[CH:105]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cn1cnc(CN)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cn(C)cn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with C-(1-methyl-1H-imidazol-4-yl)-methylamine. MS (ES+) m/e 733.49 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([NH2:17])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>C(O)(C)C.CC(O)=O.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:12]([C:13](=[O:14])[CH3:15])[C:11]([NH2:17])=[O:16])=[CH:4][C:3]=1[F:10]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1ccc(Cl)c(F)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(Cl)c(F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 67.8 %

Procedure:
A mixture of 4-chloro-3-fluorobenzaldehyde (2.47 g, 15.5 mmol), acetoacetamide (1.57 g, 15.5 mmol), AcOH (35 μL, 0.62 mmol) and piperidine (61 μL, 0.62 mmol) in isopropyl alcohol (30 mL) was stirred at room temperature for 2.5 days and evaporated under reduced pressure. The crude product was purified by a silica gel column (120 g) eluting from 50% to 80% EtOAc in hexanes to afford 2-(4-chloro-3-fluorobenzylidene)-3-oxobutanamide (2.54 g, 67.6%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:8]([O:9][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=2[Cl:29])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: OC(c1ccc(Cl)cc1Cl)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(OC(C(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)n2cncn2)cc1
Yield: 33.1 %

Procedure:
19.2 g (0.05 mol) of 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol were dissolved in 100 ml of dioxane and the solution was added dropwise to a mixture of 2 g of 80% strength sodium hydride in 100 ml of dioxane at 80° C. After the evolution of hydrogen had subsided, 10 g (0.05 mol) of 2,4-dichlorobenzyl chloride were added dropwise and the mixture was heated under reflux for 15 hours. After cooling, the solvent was distilled off in vacuo and the residue was taken up in 100 ml of water and 100 ml of methylene chloride. The organic phase was separated off, washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue was recrystallized from ether. 9 g (31% of theory) of 1-(4-chlorophenoxy)-2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol- 1-yl)-ethane of melting point 132°-135° C. were obtained.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(CCF)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCF)cc3)cc2)C1
Yield: 5.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(2-fluoro-ethyl)-benzenesulfonyl chloride (117 mg, 0.52 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (11 mg, 6%) as a colourless gum.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[O:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:10]=2)[O:5][N:4]=1
Reactant: Cc1c(C(F)F)noc1-c1ccc(C(=O)O)s1
Reactant: C1CCNCC1
Product: Cc1c(C(F)F)noc1-c1ccc(C(=O)N2CCCCC2)s1
Yield: 72 %

Procedure:
Prepared from 5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid (Preparative Example 27) and piperdine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J=53.2, 1 H), 7.31 (d, J=4.0, 1 H), 7.45 (d, J=4.0, 1 H). 13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.7, 110.3 (t, J=236), 126.8, 128.8, 130.6, 140.6, 158.6 (q, J=30), 162.1, 162.5. 19F NMR −117.4 (J=53.5). LC/MS 6.36 min, [M+1]+ 327.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[C:22]([N:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH2:30][C:29]=2[CH:28]=[N:27]1)([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([N:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:31]3([CH2:36][CH2:35][N:34]([C:15]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8]5[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:21][CH:20]=5)=[CH:19][CH:18]=4)=[O:17])[CH2:33][CH2:32]3)[CH2:30][C:29]=2[CH:28]=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2ccc(C(=O)N3CCC4(CC3)CC(=O)c3c(cnn3C(C)(C)C)C4)cc2)cc1

Procedure:
A solution of 4-(4-(methoxycarbonyl)benzyloxy)benzoic acid (25 mg, 0.087 mmol), 1-tert-butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (26 mg, 0.087 mmol), diisopropylethylamine (53 μL, 0.30 mmol), 1,2,3-benzotriazole-1-ol, monohydrate (14 mg, 0.087 mmol), 4-dimethylaminopyridine (1.1 mg, 0.01 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg, 0.96 mmol) in dichloromethane (0.2 mL) was heated at 30° C. for 18 hr. The reaction mixture was partitioned between ethyl acetate/aqueous 0.3N hydrochloric acid, the organic phase was dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC to afford methyl 4-((4-(1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)phenoxy)methyl)benzoate. HPLC column: Waters Atlantis C18 4.6×50 mm, 5 um, solvent: acetonitrile:water (0.05% TFA); flow rate 2 mL/min; gradient (% organic) start=5%, end=95%, gradient time=4 min, retention time=3.68 min; m/z=530 (M+1).