Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][P:3]([CH2:6][OH:7])(=[O:5])[OH:4].[OH-].[CH2:9]([N+:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>O.CC(O)C>[OH:1][CH2:2][P:3]([CH2:6][OH:7])(=[O:4])[O-:5].[CH2:22]([N+:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: O=P(O)(CO)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=P([O-])(CO)CO

Procedure:
To a flask were added 0.48 g bis(hydroxymethyl)phosphinic acid, 1.6 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 10 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 10 ml of 2 propanol were added and removed by distillation under reduced pressure. An oil was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:3][C:4]([C@:6]1([NH2:11])[CH2:8][C@@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@H]1C[C@@]1(N)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 2 (9.39 g, 36.8 mmol) was dissolved in 4N HCl/dioxane (90 mL, 360 mmol) and was stirred for 2 hours at room temperature. The reaction mixture was concentrated to provide (1R,2S)/(1S,2R) 1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride in quanitative yield (7 g, 100%). 1H NMR (methanol-d4) δ 1.32 (t, J=7.1, 3H), 1.72 (dd, J=10.2, 6.6 Hz, 1H), 1.81 (dd, J=8.3, 6.6 Hz, 1H), 2.38 (q, J=8.3 Hz, 1H), 4.26-4.34 (m, 2H), 5.24 (dd, 10.3, 1.3 Hz, 1H) 5.40 (d, J=17.2, 1H), 5.69-5.81 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].Cl[C:25]1[N:26]([CH2:33][C@:34]2([CH3:37])[CH2:36][O:35]2)[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[N:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:36][C@:34]2([CH3:37])[O:35][C:25]3=[N:29][C:28]([N+:30]([O-:32])=[O:31])=[CH:27][N:26]3[CH2:33]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2Cl)CC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
Tert-butyl 4-(2-chloro-4-hydroxyphenyl)-piperazine-1-carboxylate (2.7 g, 8.63 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (397 mg, 9.92 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (2.1 g, 9.50 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-ethyl acetate to afford tert-butyl (R)-4-[2-chloro-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (2.34 g, yield 55%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].NC(N)=O.C1C=CC2O[C:25](=O)[NH:24][C:22]=2C=1>>[OH:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:7]=1[NH:8][C:9]([N:24]([CH3:25])[CH3:22])=[O:11]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Reactant: O=c1[nH]c2ccccc2o1
Agent: NC(N)=O
Product: CN(C)C(=O)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
6-Nitrobenzoxazolinone was converted into the urea as described above for benzoxazolinone, using 267 g of the nitro analogue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:19][C:17](=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C[OH:21].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]([OH:19])[CH2:15][CH2:16][C:17]([OH:18])=[O:21])=[CH:12][CH:13]=1
Reactant: CO
Reactant: O=C1CCC(c2ccc(-c3ccccc3Cl)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 5.44 gm (0.02 mol) of γ-(2'-chloro-4-biphenylyl)-γ-butyrolactone (b.p. 212°-213° C. at 0.03 mm Hg), 50 ml of methanol, 1 gm of sodium hydroxide and 2 ml of water was boiled for 2 hours. The reaction mixture was then evaporated, the residue was distributed between dilute hydrochloric acid and ethyl acetate, and the cyclohexylamine salt was precipitated from the washed and dried ethyl acetate solution. Yield: 5.8 gm m.p. of the cyclohexylamine salt: 158°-159° C. (from water).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:38][CH3:39])[C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=O.[NH3:40]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]4[C:7]([O:38][CH3:39])=[CH:6][C:5]([C:3](=[O:2])[NH2:40])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:30])([CH3:29])[CH3:31]
Reactant: N
Reactant: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Solvent: CO
Product: COc1cc(C(N)=O)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-8-methoxy-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (200 mg) and a solution of ammonia in methanol (7M, 2.65 mL) was heated at 120° C. for 6 hours under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3C2CCCCO2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.5 %

Procedure:
The crude 2-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (193 mg, 0.418 mmol) was dissolved in MeOH (5.0 mL) and TFA (0.50 mL, 6.49 mmol) was added via syringe. The reaction was stirred at room temperature for 2.5 hours, and then more TFA (0.9 mL) was added, and stirring was continued overnight. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (60° C.), stirring was continued for 75 minutes. (This 75 minute period was interrupted by an approximate 15 minute period where the flask was not in the oil bath.) The reaction was cooled to room temperature and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give 2-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)ethanol (56.0 mg, 35% yield over 2 steps). MS (ESI pos. ion) m/z 378 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (s, 1H), 9.66 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.20-8.14 (m, 2H), 6.86 (d, J=8.8 Hz, 1H), 3.85 (s, 3H), 3.66 (t, J=6.86 Hz, 2H), 2.85 (s, 3H), 2.76 (t, J=6.86 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]=[O:14].[CH3:15][O:16][C:17](=[O:33])[CH2:18][N:19]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(NCC=C)C=C.CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2].CC(=O)OCC>[CH3:15][O:16][C:17](=[O:33])[CH:18]([NH:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]([OH:14])[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc2nccc(C=O)c2n1
Agent: C=CCNCC=C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(NC(c1ccccc1)c1ccccc1)C(O)c1ccnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of Zn(OTf)2 (0.064 g, 0.17 mmol) and 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (0.5 g, 2.6 mmol) and molecular sieves (4 Å, 0.66 g) in toluene (13 mL) at 0° C. was treated with (benzhydrylidene-amino)-acetic acid methyl ester (0.44 g, 1.7 mmol) and diallylamine (0.25 g, 1.7 mmol). The mixture was left at 4° C. over the weekend. The reaction was quenched by careful addition of Na2CO3 and filtered. The filtrate was diluted with EA and water and the 2 phases separated. The org. phase was dried over MgSO4 and concentrated. The residue was dissolved in MeOH (10 mL) and AcOH (0.175 g, 3 mmol) and NaCNBH3 (0.166 g, 2.6 mmol) was added. The mixture was stirred at rt overnight and partitioned between a NaHCO3 solution and EA. The org. phase was dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1) gave the title intermediate as a yellow oil (0.5 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([N:25]2[CH:29]=[C:28]([CH2:30][C:31](O)=[O:32])[C:27]([C:34]([F:37])([F:36])[F:35])=[N:26]2)[CH2:24][CH2:23]1.CCCP(O)(O)=O>C1COCC1>[CH:22]1([N:25]2[CH:29]=[C:28]([CH2:30][C:31]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:18]5[CH:17]=[N:16][CH:15]=[N:14][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:32])[C:27]([C:34]([F:37])([F:36])[F:35])=[N:26]2)[CH2:24][CH2:23]1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1cn(C2CC2)nc1C(F)(F)F
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cn(C4CC4)nc3C(F)(F)F)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid (Preparation 148, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc) gave the title compound as a white solid in 77% yield, 68 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][N:18]=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1

Procedure:
A stirred solution of compound 34 (15.0 g, 50.0 mmol) and hydrazine hydrate (10.0 g, 56 mmol) in methanol 150 mL was heated to reflux for 1 h. After cooling in an ice bath for 10 min, the solvent was removed, water (100 mL) added, and the reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated crude. The crude product was purified by column chromatography using 10% ethyl acetate in hexane, to afford the crude pyrazole intermediate 34a.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]([OH:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl>[S:2]([O:17][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)[CH3:16])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 71 %

Procedure:
A solution of 4.63 ml (59.8 mmol) of methane sulphonyl chloride diluted with 20 ml of dichloromethane is added dropwise to a solution of 10 g (59.8 mmol) of 3-nitrophenylethanol and 8.31 ml (59.8 mmol) of triethylamine in 120 ml of dichloromethane, cooled down with an ice bath. Agitation is maintained for 1 hour at 0° C. and for 2 hours at 20° C. The reaction mixture is then concentrated under vacuum and the residue is taken up in 125 ml of ethyl acetate and 100 ml of water. After agitation and decantation, the organic phase is washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent heptane/ethyl acetate 6/4) and the pure fractions are collected and evaporated in order to produce a yellow oil with a yield of 71%.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1.[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[N:8][C:5]=2[CH2:6]1)=[O:21]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC1Cc2c(nnn2-c2ccccn2)CN1
Product: CC1Cc2c(nnn2-c2ccccn2)CN1C(=O)c1cccc(Cl)c1Cl

Procedure:
Example 120 was prepared from 6-methyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine and 2,3 dichlorobenzoic acid using the conditions described in Example 65. MS (ESI) mass calcd. C18H15Cl2N5O, 387.07. m/z found, 388.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1([O:43][S:44](=[O:47])(=[O:46])[NH2:45])[CH2:42][CH2:41]1)([CH3:39])[CH3:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:45][S:44]([O:43][C:40]2([CH:37]([CH3:39])[CH3:38])[CH2:42][CH2:41]2)(=[O:47])=[O:46])=[O:35])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C1(OS(N)(=O)=O)CC1
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(C(C)C)CC1

Procedure:
2-[2-Ethyl-1-(1-isopropyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 1-isopropyl-cyclopropyl ester to afford acylsulfamate (185 mg, 56%): LCMS found 660.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:51][C:48]2[O:49][C:50]3[C:42]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=4)=[CH:43][CH:44]=[C:45]([O:52][CH3:53])[C:46]=3[N:47]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 381 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:29][C:28]=2[CH:44]([CH3:46])[CH3:45])=[O:25])[C:6]1=[O:47])[CH2:2][CH2:3][CH3:4].C=O.Cl.[C:51]([BH3-])#N.[Na+]>CO.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:34])[CH3:35])=[CH:31][C:30]([N:36]([CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH3:51])=[CH:29][C:28]=2[CH:44]([CH3:46])[CH3:45])=[O:25])[C:6]1=[O:47])[CH2:2][CH2:3][CH3:4]
Reactant: [BH3-]C#N
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NCc3cccnc3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N(C)Cc3cccnc3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-(3-pyridylmethylamino)-phenyl]urea (476 mg, 0.752 mmol) in methanol (5 ml) are added a 37% aqueous formaldehyde solution (122 mg, 1.50 ml) and conc. hydrochloric acid (0.13 ml, 1.50 ml) at room temperature. The mixture is cooled with ice, and the thereto is added sodium cyanoborohydride (71.0 mg, 1.13 ml), and the mixture is stirred at room temperature for 5 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is extracted twice with sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (445 mg, 0.684 mmol) as colorless amorphous.
Reaction SMILES: [C:1](SCC)(=[S:3])[CH3:2].[F-].[Na+].[F:9][C:10]1[CH:11]=[C:12]([N:24]2[CH2:28][C@H:27]([CH2:29][NH2:30])[O:26][C:25]2=[O:31])[CH:13]=[CH:14][C:15]=1[CH:16]1[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH2:17]1.[OH-].[K+]>C(O)C.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:1](=[S:3])[CH3:2])[O:26][C:25]2=[O:31])[CH:13]=[CH:14][C:15]=1[CH:16]1[CH2:17][CH2:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21]1
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(=S)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of ethyl dithioacetate (100 mL, 0.876 mmol) and sodium fluoride (37 mg, 0.876 mmol) in ethanol (8.8 mL) under a nitrogen atmosphere was treated with a mixture of (S)-(−)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Step 1, (300 mg, 0.876 mmol) and aqueous potassium hydroxide (1M, 0.88 mL) in ethanol (43.8 mL). The resulting mixture was stirred at ambient temperature for 26 hours, during which additional ethyl dithioacetate (50 mL, 0.438 mmol), sodium fluoride (19 mg, 0.438 mmol), aqueous potassium hydroxide (1M, 0.44 mL) and ethanol (3.0 mL) was added, and was then diluted with methylene chloride (150 mL), washed with water (50 mL), aqueous potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was recrystallized from methylene chloride/diethyl ether to give the title compound, mp 186-187° C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:15]3[C:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>C1COCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:8][CH:9]=4)=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)CCCc1ccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4ccc(CCCC(=O)O)cc4)c23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 175.6 mg (0.356 mmol) of 4-(4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)butanoic acid methyl ester in 3.5 ml of THF, add 1.07 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue, and then 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry at 40° C. under reduced pressure overnight. 130 mg (76.2% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:30]C(=O)OCC[Si](C)(C)C.[N+](CC)(CC)(CC)CC.[F-]>CC#N>[NH2:30][CH:7]1[C:6]2[C:29](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:26])[F:27])[CH2:11][CH2:10]2)[CH2:8]1
Reactant: C[Si](C)(C)CCOC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 100 °C
Yield: 88.3 %

Procedure:
(±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 0.026 mmol) and Et4NF (30 mg) were dissolved in MeCN (3 mL). The solution was heated at 100° C. for 10 min in a microwave. The solution was concentrated and the residue was purified by preparative HPLC to give (±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (11 mg, 70%) as its TFA salt. LC-MS Method 1 tR=1.38, min, m/z=479, 481; 1H NMR (CD3OD) 1.53 (m, 1H), 1.67 (m, 1H), 2.08 (m, 1H), 2.55 (m, 1H), 2.9-3.5 (5H), 4.38 (d, 1H), 4.72 (d, 1H), 7.2-8.0 (9H).