Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[Br:17][CH2:18][C:19](=[O:21])[CH3:20]>CN(C=O)C>[Br-:17].[CH2:18]([N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1)[C:19]([CH3:20])=[O:21]
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Reactant: CC(=O)CBr
Solvent: CN(C)C=O
Product: CC(=O)C[N+]1(C)CCN(c2nc3ccccc3o2)CC1
Product: [Br-]
Reaction time: 1 h

Procedure:
A 100 mg portion of 2-(4-methyl-1-piperazinyl)-benzoxazole was dissolved in 3 ml of DMF. Under cooling with ice, 95 mg of bromoacetone was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 60 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 119 mg of the title compound.
Reaction SMILES: [C:1]12([C:11]([NH2:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(C)C.CO>C1COCC1>[C:1]12([CH2:11][NH2:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of admantane-1-carboxamide (2 g, 11.17 mmol) in THF (50 mL) was added BH3.Me2S (10.2 M, 3.4 mL, 34.7 mmol) under nitrogen. The mixture was heated at reflux overnight. The solution was cooled to rt. Methanol (20 mL) was added to the solution. The mixture was concentrated under vacuum to give crude product, which was purified by chromatography on silica gel to afford (1-adamantyl)methylamine (1.09 g, 59%). 1H NMR (CDCl3, 400 MHz): δ=1.44-1.96 (m, 15H), 2.30 (s, 2H).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]([Cl:28])([Cl:27])[C:24](Cl)=[O:25]>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:24](=[O:25])[C:23]([Cl:28])([Cl:27])[Cl:22])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 9a) (8.5 g, 29.9 mmol) in anhydrous dichloromethane (33 ml) was added trichloro-acetyl chloride (16.3 g, 89.7 mmol). The resulting mixture was stirred overnight at room temperature, after which a second portion of trichloro-acetyl chloride (3 ml) was added. The resulting mixture was stirred for 6 h at 40° C., and then at 25° C. over 2 days, evaporated to dryness. Methyl tert-butyl ether (60 ml) was added and the mixture was stirred. The product precipitated, was filtered off, washed with a small amount of methyl tert-butyl ether and dried in vacuo to give 9.8 g (76%) of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.34 min; m/z=429.01 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: Cn1ccc2c(Br)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 51 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of n-butyllithium in pentane (28.8 ml) over 30 minutes and stirred for 30 minutes. The mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) added with ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was acidified with 5 N aqueous hydrochloric acid under ice cooling and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 52, 3.17 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]([F:38])=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][C:29]=2[F:39])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:29]([F:39])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][C:37]=2[F:38])[CH2:24][CH:23]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(C(=O)O)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a mixture of 247 mg of the crude methyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoate, 4.0 mL of THF, and 2.0 mL of methanol was added dropwise a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. The reaction mixture was neutralized by addition of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 233 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid as a white solid. FAB+: 601
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10]C=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]C(C)=O.CI.[C:19](=[O:22])([O-])[O-].[Na+].[Na+]>O>[C:1]1([N:7]2[C:11]([S:12][CH3:13])=[N:10][C:19]([OH:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Reactant: Sc1ncnn1-c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSc1nc(O)nn1-c1ccccc1
Reaction time: 1 h

Procedure:
An amount of 23.2 g of 1-phenyl-5-mercapto-1,2,4-triazole, M.P. 220°C, is placed into 50 ml of acetone, 50 ml of water and 10 ml of methyliodide. An addition is then made in portions, within 15 minutes, of 21 g of sodium carbonate, and, after completion of the addition, stirring continued for 1 hour at 30°C. The acetone is evaporated off, and the solution acidified with dilute hydrochloric acid. The precipitated product is filtered off, and recrystallised from 250 ml of ethanol to obtain 1-phenyl-5-methylmercapto-3-hydroxy-1,2,4-triazole in the form of white crystals having a melting point of 176°-177°C.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](Cl)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].N1C=CC=CC=1>CC(C)=O>[C:1]([O:9][CH2:10][C:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Reactant: O=C1CCCN1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(OCC(=O)N1CCCC1=O)c1ccccc1
Yield: 64.7 %

Procedure:
A mixture of (benzoyloxy)acetyl chloride (1.98 g, 0.01 mole), pyrrolidone (0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) in acetone (10 ml) was refluxed for 3 h. The cooled mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and the solution washed with a 2% aqueous solution of sodium bicarbonate, 2M hydrochloric acid and water. After drying over anhydrous sulphate, the organic phase was evaporated under reduced pressure to give a residue which crystallized by addition of ether. Recrystallization from ether-petroleum ether yielded 1.6 g (65%) of the title compound. Mp 83°-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl.O>O1CCOCC1>[OH:11][C:10]1[C:17]2[C:13](=[CH:12][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:16])[NH:15][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2=COc3ccccc3C(=O)N2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2O)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
To a suspension of 1 g (3.74 mmol) of 3-(3-Methoxy-phenyl)-4H-benzo[f][1,4]oxazepin-5-one in dioxane (20 mL), 0.225 g (5.6 mmol) of sodium hydride (60% dispersion in mineral oil) were added under strictly oxygen-free atmosphere and the mixture was heated at 100° C. for 45 min. After cooling to room temperature, 2N hydrochloric acid was added till pH 1 then water was added until complete precipitation of the product was reached. The solid was filtered, washed with water and dried in vacuo, affording 0.82 g of the title compound (82%).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33][CH:32]=1.[C:43]([BH3-])#[N:44].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:44]([CH2:43][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ccnc2ccccc12
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ccnc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with quinoline-4-aldehyde (47.2 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (76.4 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:51])=[CH:13][C:14]2[N:15]([CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[C:42]([O:43][C@H:44]([CH2:46][CH:47]=C)[CH3:45])=[CH:41][C:40]([CH3:49])=[CH:39][C:38]=4[F:50])[CH:32]=3)[N:30]=2)[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:27])([O:23][CH2:24][CH:25]=C)[CH2:19][CH2:18]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OCC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:51])=[CH:13][C:14]2=[N:30][C:29]3=[CH:28][N:15]2[C:16]=1[N:17]1[CH2:18][CH2:19][C:20]([CH3:27])([O:23][CH2:24][CH:25]=[CH:47][CH2:46][C@H:44]([CH3:45])[O:43][C:42]2[CH:41]=[C:40]([CH3:49])[CH:39]=[C:38]([F:50])[C:37]=2[C:33]2[CH:32]=[C:31]3[CH:36]=[CH:35][CH:34]=2)[CH2:21][CH2:22]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(F)cc(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)cc(F)c1-c1cccc-3c1
Yield: 70 %

Procedure:
Prepared in 70% yield from methyl(2S)-2-(tert-butoxy)-2-[2-(3-{2-fluoro-4-methyl-6-[(2S)-pent-4-en-2-yloxy]phenyl}phenyl)-7-methyl-5-[4-methyl-4-(prop-2-en-1-yloxy)piperidin-1-yl]imidazo[1,2-a]pyridin-6-yl]acetate following the procedure for ethyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 670.25.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
A mixture of 3-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.2 mmol), 4-fluorobenzoic acid (34 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give 3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 32%) as a white solid. MS found, 573.5 and 575.5.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH4+:72].[Cl-:73]>CN(C)C=O>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][C:25]2[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:24]=2[CH:11]2[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:73])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:41])[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12]2)=[CH:37][CH:36]=1)(=[O:39])[NH2:72]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2Oc2ccc(C(=O)O)cc2)N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Yield: 87.9 %

Procedure:
In a manner similar to the method described in Example 47a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(4-hydroxycarbonyl-phenoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 0.57 mmol) was reacted with EDCI (0.22 g, 1.14 mmol), HOBT (0.154 g, 1.14 mmol), diisopropylethylamine (0.29 g, 2.28 mmol), NH4Cl (60 mg, 1.14 mmol) in N,N-dimethylformamide to give racemic(2′R, 3R, 4′S)-2′-[2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.35 g, 88%)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:47])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:47])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 50.9 %

Procedure:
Starting with 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.35 g (0.69 mmol) of 2-(4-bromobutoxy)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.202 g; 63.4% overall yield) was obtained as a white solid, mp 177°-180° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[O:33][CH3:34])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+].C(O)C>O1CCCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][C:24]=3[O:33][CH3:34])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Ethyl 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (100 mg, 0.173 mmol) was diluted with tetrahydrofuran (1 mL) followed by the addition of sodium hydroxide (692 μL of a 1 M aqueous solution, 0.692 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using two 0.5 mm preparative silica gel plates eluting with 10% methanol/dichloromethane to yield 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (61 mg, 0.111 mmol, 64.1% yield). 1H NMR (400 MHz, D6 DMSO) δ 8.48 (t, 1H), 7.82 (d, 2H), 7.44 (s, 1H), 7.35 (d, 1H), 7.23 (m, 2H), 6.96 (d, 2H), 6.61 (s, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 3.87 (s, 3H), 3.82 (t, 1H), 3.47 (q, 1H), 3.17 (d, 1H), 2.89 (t, 2H), 2.21 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:38])([CH3:39])[CH2:36][CH3:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(C(=O)N3CCOCC3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
Following the same procedure in Example 3, Step A, using morpholine (26.1 mg, 0.30 mmol), diisopropylethylamine (69.7 μL, 51.7 mg, 0.40 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (65.7 mg, 0.20 mmol)) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (91.3 mg, 0.24 mmol). The mixture was stirred overnight at room temperature, added H2O (50 mL), extracted with EtOAc (3×50 mL). The desired title compound was purified by reversed-phase HPLC (C-18 column) using 10-50% CH3CN/H2O to give 82.1 mg (80%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3 H), 1.27 (m, 5 H), 1.65 (m, 3 H), 1.69 (s, 6 H), 1.78 (m, 2 H), 2.04 (q, J=7.42 Hz, 2 H), 2.12 (m, 1 H), 3.47 (m, 2 H), 3.62 (m, 2 H), 3.79 (m, 4 H), 4.50 (d, J=7.62 Hz, 2 H), 7.66 (dd, J=8.69, 1.46 Hz, 1 H), 7.82 (d, J=0.78 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)+=398.3. Anal. Calcd for C24H35N3O2+1.60 TFA+1.10 H2O+0.30 MeCN (612.14): C, 54.55; H, 6.54; N, 7.55. Found: C, 54.61; H, 6.53; N, 7.51.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([N:23]([CH2:59][CH2:60][CH2:61][O:62][Si](C(C)(C)C)(C)C)[C:24](=[O:58])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]2[CH2:56][CH2:55][C:40]3([O:45][CH2:44][CH2:43][N:42]([C:46]([C:48]4[N:49]=[C:50]([CH2:53][CH3:54])[S:51][CH:52]=4)=[O:47])[CH2:41]3)[CH2:39][CH2:38]2)[C:31]=1[Cl:57])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:33][CH2:32][CH2:31][CH:30]([CH3:35])[CH3:29].[CH2:19]([N:23]([CH2:59][CH2:60][CH2:61][OH:62])[C:24](=[O:58])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]2[CH2:38][CH2:39][C:40]3([O:45][CH2:44][CH2:43][N:42]([C:46]([C:48]4[N:49]=[C:50]([CH2:53][CH3:54])[S:51][CH:52]=4)=[O:47])[CH2:41]3)[CH2:55][CH2:56]2)[C:31]=1[Cl:57])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(CC)n2)CCO3)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CCCCN(CCCO)C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(CC)n2)CCO3)c1Cl
Reaction time: 8 h

Procedure:
TBAF (1M in THF, 0.62 mL) was added to a solution of N-butyl-N-(3-(tert-butyldimethylsilyloxy)propyl)-3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanamide [Example 80, step a] (0.47 g) in THF (10 mL) and the mixture stirred overnight. The solvent was evaporated and the residue purified by flash silica chromatography, elution gradient 1:1:0.05 ethyl acetate:isohexane:triethylamine to 95:5 ethyl acetate:triethylamine, to give the subtitled compound as a clear oil. Yield 0.40 g.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:29])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH3:31][Si](C=[N+]=[N-])(C)C>>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:31])[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])=[N:21][C:22]1[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COc1cc2ncnc(NC(=Nc3c(C)cccc3C)NCCN(C)C)c2cc1OC
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 11, N-(2-dimethylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-(7-hydroxy-6-methoxyquinazolin-4-yl)guanidine was reacted with trimethylsilyldiazomethane to give the title compound in 63% yield; NMR Spectrum: (DMSOd6, 100° C.) 2.21 (s, 6H), 2.24 (s, 6H), 2.54 (t, 2H), 3.57 (q, 2H), 3.75 (s, 3H), 3.9 (s, 3H), 7.08 (s, 1H), 7.17 (s, 3H), 7.58 (s, 1H), 8.43 (s, 1H), 10.8 (br s, 1H); Mass Spectrum: M+H+ 423.