Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)C.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[C:16]([O:15][C:13](=[O:14])[NH:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([CH2:5][CH:4]=[O:3])[CH2:11][CH2:10]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-(4-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester (1.04 g, 4 mmol), in toluene (10 mL) at −78° C. a 1.2M solution of DIBAL-H (5.1 mL, 6 mmol) in toluene was added. The mixture was stirred at −78° C. until TLC after 0.5 h indicated completion of the reaction. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was used without purification on the next step. MS (m/e): 242.3 (M+H+).
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(O)(C(F)(F)F)=O>C(OCC)(=O)C.[Pd]>[C:4]1(=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][NH:5]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1NCc2ccccc21
Reaction time: 48 h
Yield: 7.2 %

Procedure:
A solution of phthalimide (1.0 g, 6.8 mmol) and TFA (5 mL) in ethyl acetate (100 mL) was added 10% Pd—C (1 g). The reaction mixture was hydrogenated at 55 psi for 2 days. Catalyst was then filtered through diatomaceous earth (Celite®) and the filtrate was concentrated to give yellowish solid as crude product (0.37 g). 120 mg of them was then purified by Prep. TLC (eluted with dichloromethane) to give pure 2,3-dihydro-isoindol-1-one (65 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Product: COC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)oc2c1O

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tributylphenyltin under conditions analogous to example 3b. MS: (+) m/z 347.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](F)[CH:20]=3)[N:16]=[C:15]([NH2:28])[N:14]=2)[CH2:8]1)[CH3:3].[NH2:30][NH2:31]>C(O)C>[CH3:3][CH:2]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]4[C:22]([C:25]([NH2:26])=[N:30][NH:31]4)=[CH:21][CH:20]=3)[N:16]=[C:15]([NH2:28])[N:14]=2)[CH2:8]1)[CH3:1]
Reactant: CC(C)OC(=O)N[C@@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: CCO
Product: CC(C)OC(=O)N[C@@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 100 °C

Procedure:
Into a 5 mL sealable vial was added 1-methylethyl{(3R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinyl}carbamate (116 mg, 0.291 mmol) followed by ethanol (3 mL) and hydrazine (0.428 mL, 8.73 mmol). The mixture was then capped and heated at 100° C. overnight. The reaction was concentrated, then dissolved in 2 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 10% CH3CN/H2O, 0.1% TFA to 35% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3. It was then extracted with EtOAc (3×15 mL) and the organic fractions were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was then transferred to a haystack vial and 1 mL of water was added and freeze dried. LC-MS (ES) m/z=411 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (d, 3H), 1.16 (d, J=6.3 Hz, 3H), 1.39-1.49 (m, 2H), 1.70-1.77 (m, 1H), 1.85-1.93 (m, 1H), 2.87 (bs, 1H), 3.03 (bs, 1H), 4.06-4.16 (m, 1H), 4.28 (bs, 1H), 4.77 (ddd, J=12.51, 6.19, 6.06 Hz, 1H), 5.38 (s, 2H), 6.09 (bs, 2H), 6.56 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[C@H:29]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1ccccc1)C(=O)O2

Procedure:
(5S,8S)-tert-butyl 7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (G1) (70 mg, 126 μmol, 1 eq.) was diluted in 1:1 DCM:TFA (2 mL) and stirred overnight at room temp. then concentrated to give (5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (H1) in quantitative yield. LC MS+/−: 500.41/498.55 at 3.09 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:4])=[O:8]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1C(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (7.8 mmol, 1.0 g), 5-chloro-2-methylindole (13.8 mmol, 2.28 g), and AlCl3 (9.0 mmol, 1.2 g) were stirred in 100 mL DCE overnight at 65° C. The reaction was cooled and quenched with 10 mL water. The resultant precipitate was filtered and washed with a small amount of DCE giving 1.06 g of the sub-titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C(#N)C>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH3:20])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH2:29][O:30][CH3:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc(OCc2ccccc2)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (900 mg, 3.0 mmol) and anhydrous potassium carbonate (994 mg, 7.2 mmol) in acetonitrile (20 ml) was treated with chloromethyl methyl ether (0.24 ml, 6.6 mmol) and the mixture was stirred and held at 50° C. for 24 hours whereupon further anhydrous potassium carbonate (994 mg, 7.2 mmol) and chloromethyl methyl ether (0.96 ml, 26.4 mmol) were added and the mixture was stirred and held at 50° C. for a further 4 days. Upon cooling to room temperature the solvent was removed in vacuo and the residue treated with water (30 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford crude methyl 4-benzyloxy-5-isopropyl-2-(methoxymethyloxy)benzoate as a pale yellow oil that was used in the next step without further purification. 1H NMR (DMSO-d6) 7.57 (1H, s), 7.48 (2H, d), 7.44 (2H, t), 7.38 (1H, t), 6.90 (1H, s), 5.23 (4H, s), 3.78 (3H, s), 3.39 (3H, s), 3.21 (1H, m), 1.17 (6H, d). MS: [M+Na]+ 367.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCN)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCNC(C)=O)C1=O
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Acetic anhydride (0.2 g) was added dropwise to a solution of 3-(2-aminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.50 g, 1.43 mmol) in pyridine (2 ml) with stirring under cooling with ice. The mixture was left standing overnight at room temperature. To this solution was added saturated aqueous NaHCO3 (30 ml), and the mixture was extracted with benzene. After drying of the extract, the solvent was removed therefrom by evaporation under reduced pressure, giving the intended 3-(2-acetylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.52 g, 92% yield) in oily form. IR (CHCl3) [cm-1 ]; 3430, 2920, 2850, 1665, 1590, 1580, 1365. NMR (δ, CDCl3 ppm); 1.95 (3 H, s), 3.93 (0.45 H, dd, 990 and 3.63 Hz), 4.03 (0.55 H, ddd, 9.24, 3.63 and 1.65 Hz), 5,75 (0.55 H, d, 1.65 Hz), 5.76 (0.45 H, s), 6.06-6.11 (1 H, m).
Reaction SMILES: CS([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7])(=O)=O.[CH:21]1[C:22]([I:30])=[CH:23][C:24]([I:29])=[C:25](O)[C:26]=1[I:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:27][C:26]1[CH:25]=[C:24]([I:29])[CH:23]=[C:22]([I:30])[C:21]=1[O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7]
Reactant: CCCCCCCCCCCCCC(C)OS(C)(=O)=O
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 2-methanesulfonyloxypentadecane (15.5 g, 48.1 mmol) in dry DMF (200 ml) was added triiodophenol (22.6 g, 47.9 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction flask was immersed in an oil bath which was heated to 85° C. over a period of 0.5 hr. The reaction was stirred under N2 atmosphere for 16 hrs. At the end of this period the reaction was processed as for Example 1 except at 4 times the volumes to provide a brown residue. Flash column chromatography (silica, hexanes) provided 2-(2,4,6-triiodophenoxy)pentadecane (19.2 g, 58.8%) as a white solid. Mp: 56°-58° C. p Title Compound:1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. Calculated for C21H33I3O: C, 36.97; H, 4.88; I, 55.81. Found: C, 36.89, H, 4.80; I, 55.85.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>ClCCl>[Br:12][C:10]1[N:11]=[C:7]([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[S:8][CH:9]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Br)cs2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) was added dropwise to a −78° C. solution of 2,4-dibromothiazole (0.524 g, 2.16 mmol) in dichloromethane (11 mL). The mixture stirred at −78° C. for 20 minutes, and then tert-butyl 4-oxopiperidine-1-carboxylate (0.516 g, 2.59 mmol) was added in 8 portions. The reaction mixture stirred at −78° C. for 10 minutes. The cooling bath was removed, and the reaction was allowed to warm to rt over 1 h. The reaction mixture was cooled to −30° C. and was then quenched by the addition of saturated aqueous ammonium chloride solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 5-60% ethyl acetate-hexane) to afford tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.744 g, 95%). MS (ESI, pos. ion) m/z 363, 365 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2([NH:14][C:15](=[O:17])[CH3:16])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CS(O[CH2:25][CH2:26][CH:27]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[CH2:28][N:29]([CH3:38])[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O>O>[ClH:45].[CH3:38][N:29]([CH2:28][CH:27]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[CH2:26][CH2:25][N:11]1[CH2:12][CH2:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10]1)[C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 70 °C

Procedure:
22.7 g of 4-phenyl-4-acetylaminopiperidine hydrochloride are dissolved in 20 ml of water. 10 ml of concentrated sodium hydroxide solution are added. The mixture is extracted twice with dichloromethane and the organic phase is dried over MgSO4, The solution obtained is added to the product obtained in step 8. The mixture is concentrated to dryness, 30 ml of DMF are added and the mixture is heated to 70° C. for 1 h 30 min. The solution is poured very slowly onto 30 ml of water+ice. The precipitate is filtered off, taken up several times in water and drained. It is purified by chromatography on silica; elution: pure dichloromethane, then dichloromethane with addition of methanol up to 10%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCCC1>[CH:17]([CH2:19][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10])=[O:18]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: C=CC=O
Solvent: C1CCOC1
Product: N#CC(C#N)(CCC=O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
First, 20 ml of tetrahydrofuran was added dropwise slowly to the mixture of 0.50 g of dihydro tetrakis(triphenylphosphine)ruthenium and 3.00 g of (4-(trifluoromethyl)benzyl)malononitrile under an atmosphere of nitrogen , followed by stirring for 15 minutes. Then, 0.82 g of acrolein was added dropwise slowly, followed by stirring for 1 hour at room temperature and then the solvent was distilled away. The residue was subjected to silica gel column chromatography to give 1.58 g of 2-(2-formylethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the intermediate (19)).
Reaction SMILES: [N:1]1([C:6]2[C:7]([OH:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CO[C:15]1(OC)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1.B(F)(F)F.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:11]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17][CH2:16]3)[O:12][C:7]=2[N:8]=[CH:9][CH:10]=1
Reactant: COC1(OC)CCN(C(=O)OCc2ccccc2)CC1
Reactant: Oc1ncccc1-n1cccc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-pyrrol-1-ylpyridin-2-ol (481 mg, 3.00 mmol) and benzyl 4,4-dimethoxypiperidine-1-carboxylate (922 g, 3.3 mol) in CH2Cl2 (20 mL) at 40° C. was added BF3.OEt2 (407.3 μL, 3.300 mmol) drop-wise. The reaction mixture was stirred at 40° C. for 16 hours. The mixture was poured into sat. aq. Na2CO3 and was stirred for 5 min before it was extracted with EtOAc (3×). Organic layers were combined, washed with sat. aq. Na2CO3, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/CH2Cl2) to give benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate as an oil. ESI-MS m/z calc. 375.2. found 376.5 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 8.10 (dd, J=7.7, 1.1 Hz, 1H), 8.00 (dd, J=4.9, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.42-7.36 (m, 4H), 7.36-7.29 (m, 1H), 7.16 (dd, J=7.8, 4.9 Hz, 1H), 6.33 (t, J=3.2 Hz, 1H), 6.20 (d, J=3.4 Hz, 1H), 5.11 (s, 2H), 3.97 (d br, J=13.2 Hz, 2H), 3.28 (s br, 2H), 1.98-1.92 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Br:17])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methoxy-phenyl)-3-oxo-propionic acid ethyl ester (5.3 g, 23.9 mmol; prepared as reported in J. Org. Chem. 2001, 66, 6323-6332) in carbon tetrachloride (50 ml) was added of N-bromosuccinimide (5.1 g, 28.7 mmol) portion-wise The reaction mixture was stirred at room temperature under an Ar atmosphere for 4 hours. Water was added, the resulting mixture was extracted with CHCl3, and the organics were dried over Na2SO4 and evaporated under reduced pressure to yield the title compound as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 1.25 (t, 3H, COOCH2CH3, J=7), 3.92 (s, 3H, OCH3), 4.25 (q, 2H, COOCH2CH3, J=6.4), 5.82 (s, 1H, CHBr), 6.97-7.11 (m, 2H, Ar), 7.51-7.60 (m, 1H, Ar), 7.90-7.95 (m, 1H, Ar).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:10]=[C:11]([C:15](OC)=[O:16])[CH:12]=[N:13][CH:14]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1)[CH3:8]
Reactant: CCc1cncc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(CO)c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a suspension of LAH (1.92 g, 50.85 mmol) in anhydrous THF 40 mL at 0° C. was added dropwise a solution of methyl 5-ethylpyridine-3-carboxylate (4.20 g, 25.42 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH and then diluted with water. Ethyl acetate was added, the reaction mixture was stirred for 10 minutes, and the precipitate was filtered off. The solid was washed with ethyl acetate (3×100 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated to provide (5-ethylpyridin-3-yl)methanol as a thick oil (3.31 g, 95% yield), which was used in the next step without any further purification; M+ 137.18.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCN(C(C)C)C(C)C>CO>[F:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:7][CH2:6]2)=[CH:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(S(C)(=O)=O)CC3)c2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (1.3 g, 2.9 mmol, 1.0 equiv) in MeOH (10 mL) was added by syringe HCl (4.0 M in dioxane, 10 mL, 40 mmol, 13.8 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in THF (10 mL) and methanesulfonyl chloride (220 μL, 2.9 mmol, 1.0 equiv) and DIPEA (2.0 mL, 11.5 mmol, 4.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 0.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by flash chromatography on silica gel (1%-10% MeOH/DCM) to provide 1-(2-fluoro-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea (930 mg, 76%). LCMS m/z (APCI)=422.2 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH3:17])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[Cl:18][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([C:3]#[N:4])[CH3:19])[C:14]=2[O:15][CH2:16][CH3:17]
Reactant: CCOc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CCOc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (108 mg, described in Example 122) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 51%). MS (ES): M/Z [M+H]=483. 1H NMR: (400 MHz, CHLOROFORM-d): 1.59 (t, J=7.0 Hz, 3H), 1.91 (s, 3H), 4.50 (d, J=14.2 Hz, 1H), 4.63-4.81 (m, 2H), 4.83 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.90-7.99 (m, 2H) and 9.15 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23])([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22]([O:9][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:24])=[O:23])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: O=c1cccccc1O
Solvent: c1ccncc1
Product: O=c1cccccc1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 6 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (0.54 g, 2.0 mmol) in 10 mL of pyridine to afford PZBG-4d in 6% Yield (0.04 g, 0.1 mmol). 1H NMR (400 MHz, DMSO) δ=9.00 (d, J=2.4 Hz 1H), 8.66 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 8.38 (d, J=8.8 Hz 1H), 7.66 (d, J=9.6 Hz 1H), 7.50 (td, J1=8.4 Hz, J2=3.6 Hz, J3=1.2 Hz, 1H), 7.35 (td, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.20-7.15 (m, 2H). 13C (125 MHz, DMSO) δ=178.71, 155.30, 151.20, 147.90, 140.96, 138.83, 137.10, 134.58, 133.22, 131.93, 131.55, 127.92, 121.11. ESI-MS(+): m/z 353.15 [M+H]+, 375.11 [M+Na]+.