Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:13]3[NH:14][CH:15]=[N:16][CH:17]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(Cc2cnc[nH]2)c2c(c1)OCCO2
Yield: 72.3 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate A3) (1 g, 2.11 mmol) in dichloromethane (30 mL) was reacted with TFA:trifluoroacetic acid (5.3 mL, 68 mmol)) and triethylsilane (TES) (2.8 mL, 17 mmol) at rt for 24 h. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1H-imidazole (Intermediate A4) 330 mg (72%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(=O)CCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1ccnc1
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Add sodium hydride (0.212 g; 1.2 equiv; 5.29 mmoles) to a solution of 1H-imidazole (0.30 g; 1.0 equiv; 4.41 mmoles) and methyl 5-bromopentanoate (1.03 g; 1.2 equiv; 5.29 mmoles) in dimethylformamide (20 mL). Stir the mixture for 18 hours then add water (15 mL). Extract the mixture with dichloromethane and wash with brine (20 mL). Dry the organic phase over sodium sulfate, filter, and concentrate to give the crude product, which is purified by column chromatography (0 to 10% methanol in dichloromethane) to afford methyl 5-imidazol-1-ylpentanoate (0.655 g; 82%) as a yellow oil: MS (m/z): 183(M+1).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To a solution of compound 288 (0.33 g, 0.581 mmol) in DCM (11.6 mL) was added TFA (0.53 mL, 6.98 mmol, 12 eq.). The reaction mixture was stirred at r.t. for 24 h, concentrated and the residue was purified by Biotage SP1 Flash Purification System (eluent a gradient DCM/MeOH/NH4OH, 95/5/0.1 to 9/1/0.2) to afford 289 as a white solid (0.256 g, 0.548 mmol, 94% yield). Characterization of compound 289 is provided in the Table 6.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22]>C(Cl)Cl.C(OCC)C>[ClH:22].[ClH:22].[CH3:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][N:17]=1
Reactant: Cc1nccc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(N)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of [1-(2-methyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (818.7 mg, 2.8 mmol) in CH2Cl2 (14 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (7 mL) and was stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated twice with diethyl ether. The title compound was obtained after removal of the solvent under reduced pressure as a light brown solid (869 mg, 100%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C@H:45]([CH2:48][NH2:49])[O:44][C:43]=2[CH:50]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:49][CH2:48][CH:45]2[O:44][C:43]3[CH:50]=[C:39]([O:38][CH3:37])[CH:40]=[CH:41][C:42]=3[O:47][CH2:46]2)=[CH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Indolebutyric acid (1.3 g, 6.5 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 7.8 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.5 g, 6.5 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Evaporation of product fractions gave 1.5 g (61%) of the desired product, (S)-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as a foam.
Reaction SMILES: [C:1]1([N:7]=[C:8]([CH2:10][C:11](=O)[CH3:12])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]1([NH:7][C:8](=[CH:10][C:11](=[N:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:12])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)CC(C)=Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(=CC(C)=Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Then, 605 g of 2-phenylimino-4-pentanone solid and 449 g of anilinehydrochloride were dissolved in 2000 ml of ethanol, and the solution was refluxed for 2 hours. After the solution was cooled at the room temperature, green solid was precipitated. The green solid was separated and dried under vacuum pumping. Then the solid was suspended in 1000 ml of diethylether, and 150 g of NaOH solution in 1200 ml of water was added. The slurry mixture was, then, stirred for 1 hour at the room temperature. Then an organic layer was separated and dried over MgSO4. The solid was filtrated, and solvents were removed by vacuum pumping to get green solid. The green solid was recrystallized to get 650 g of solid (yield=75%). NMR analysis confirmed the structure; 1H-NMR(CDCl3) δ1.95(s, 2CH3), 4.93(s,═CH), 7.02(m, Ph), 7.31(m, Ph), and 13.2(brs, NH).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:21]([N:26]=[C:27]=[O:28])(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCCl>[C:21]([NH:26][C:27](=[O:28])[O:8][CH:7]([C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
Into a three-necked flask purged with nitrogen gas, benzoin (2.12 g; 10 mmol) was charged, and chloroform (30 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (7 g) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give benzoylbenzyl N-methacryloylcarbamate (3.3 g), which was recrystallized from a mixture of benzene and chloroform to give colorless transparent plates. M.P., 161°-163° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[N:36]1([C:7](=[O:9])[CH2:6][O:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:12]=[CH:11][CH:10]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: O=C(O)COc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1cccc(O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-hydroxyphenoxy)acetic acid (246 mg) in DMF (10 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (336 mg), 1H-benzotriazol-1-ol hydrate (268 mg) and morpholine (153 μL) at room temperature, followed by overnight stirring at room temperature. The solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(2-(morpholin-4-yl)-2-oxoethoxy)phenol (305 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(2,2-difluoro-1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([Cl:29])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
3-chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile (0.40 g, 0.94 mmol) and hydrazine monohydrate (0.11 mL, 2.3 mmol) dissolved in methanol (10 mL). The reaction was stirred at 60° C. for 1.5 h. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (0.26 g, 94%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O=C(NCCO)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-ethanolamine (12.03 g, 61.6 mmol) in dry dichloromethane (50 ml) was added diisopropylethylamine (32.2 ml, 184.9 mmol) and 2-methoxyethoxymethyl chloride (16.9 ml, 147.9 mmol) with stirring. The mixture was allowed to warm to room temperature then stirred for a further 3 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed successively with 1M hydrochloric acid, sat. aq. sodiumhydrogen carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to porvide the title compound as a orange/yellow oil which was used without further purification. 1H--NMR; δ(CDCI3), 7.35 (5H, m), 5.45 (1H, m), 5.11 (2H, s), 4.72 (2H, s), 3.67 (4H, m), 3.55 (2H, m) and 3.38 (5H, m).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1>CC#N>[CH3:37][C:38]1[C:46]2[C:45]([N:47]3[CH2:52][CH2:51][CH:50]([NH:53][C:12](=[O:14])[C:11]4[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:10]=4)[CH2:49][CH2:48]3)=[N:44][CH:43]=[N:42][C:41]=2[NH:40][CH:39]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: O=C(O)c1cccc(OCCN2CCCC2)c1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cccc(OCCN5CCCC5)c4)CC3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzoic acid D38 (200 mg) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (171 mg, 0.98 mmol) was dissolved under argon in MeCN (20 ml) and cooled down to 0° C. Then N-methylmorpholine (0.3 ml) was added and the mixture was stirred at 0° C. for 2 hours. To this mixture was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (240 mg) in small portions, afterwards the reaction was then warmed up to room temperature. After stirring for 16 hours, the reaction was filtered and concentrated to give crude product. This product was purified by prep-HPLC (A 0.01% NH4HCO3/Water, B: ACN, 0˜8 min 25-50%, 50%˜60% 8-12 min, 60%˜95% 12-15 min, 95˜95% 15-18 min) to give 50 mg of white solid of desired product E43. LCMS [MH+] 449.2@1.52 min (5 min run)
Reaction SMILES: [CH2:1]([CH:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C:5]1([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:32])[CH3:22])[CH:2]=C.C(=O)(O)[O-:34].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[F:32][C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[C:5]1([CH3:22])[CH:4]([CH2:1][CH2:2][OH:34])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1
Reactant: C=CCC1C(C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc([N+](=O)[O-])ccc2F)C(CCO)S(=O)(=O)C1(C)C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl ((5RS,6RS)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.256 mmol) in DCM (1.8 ml) and MeOH (0.6 ml) was cooled to −78° C., and sodium bicarbonate (42.9 mg, 0.511 mmol) was added and the mixture was ozonolyzed for 10 min. Oxygen was bubbled through the solution for 2 min, then solid sodium borohydride (14.5 mg, 0.383 mmol) was added to the mixture and the mixture was removed from the cooling bath and was allowed to reach RT and stirred for 30 min. The reaction was quenched with sat. solution of NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to afford crude racemic tert-butyl ((5RS,6RS)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.253 mmol, 99% yield) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]2[O:21][C:31]([CH3:35])([CH3:34])[CH:32]=[CH:33][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]3=[CH:9][C:8]=1[NH:7]2
Reactant: C#CC(C)(C)Cl
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
To a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide, under an inert atmosphere, there are added 2 g of anhydrous potassium carbonate. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyne are added, and the reaction mixture is held at 65° C. for 24 hours and then at 130° C. for 1 hour. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with 1M potassium hydroxide solution, dried over sodium sulphate and then evaporated. After chromatography over silica gel (cyclohexane/acetone: 90/10), 1.10 g of the expected product are isolated.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 60% sodium hydride dispersion in mineral oil (220 mg, 5.5 mmol) in cold (0° C.) THF is added 2-pyridone (475 mg, 5.0 mmol) in THF (4 mL) and DMPU (2 mL) followed by ethyl bromoacetate (0.556 mL, 5.0 mmol), and the reaction is stirred at RT for 1 h. The reaction is quenched with water, and extracted with EtOAc. The organic layer is separated, evaporated, and the residue purified by chromatography on silica gel; elution with EtOAC:dichloromethane:heptane (50:30:20) gives 690 mg of the product 425. 1H NMR (CDCl3) δ 7.35 (m, 1H), 7.21 (d, 1H), 6.57 (d, 1H), 6.19 (t, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 1.28 (t, 3H); MS: m/z 182 (M++1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:10][C:9]1[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@@:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccnc1CCl
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ncccc2F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (33%) as a colorless solid: mp 125-126° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 8.38-8.32 (m, 1H), 7.43-7.34 (m, 1H), 7.28-7.11 (m, 3H), 7.02-6.95 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.6, 156.2, 155.2, 145.4, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.9 (M+1). Anal. Calcd. for C23H17FN2O4: C, 68.31; H, 4.24; N, 6.93. Found: C, 67.27; H, 4.24; N, 6.93.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9]4=[C:10]([NH:17][C:18](=[O:19])[N:8]24)[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Br:20][C:13]1[CH:12]=[CH:11][C:10]2[NH:17][C:18](=[O:19])[N:8]3[C:9]=2[C:14]=1[CH2:15][CH2:16][CH:7]3[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CC3
Solvent: CC(=O)O
Solvent: CC#N
Product: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A suspension of 4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.200 g, 0.799 mmol) in acetonitrile (10.0 mL) and acetic acid (2.42 mL) was heated to dissolve residual solids and the resultant solution was cooled to 0° C. The resulting solution was treated with a solution of N-bromosuccinimide (0.144 g, 0.807 mmol) in acetonitrile (3.0 mL), added dropwise, at 0° C. and subsequently stirred at 0° C. for 1 h. The reaction mixture was concentrated to a residue which was dissolved in chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.177 g, 67%) as a racemic mixture along with an additional other brominated isomer, 8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (which was not be separated) in a 4.4:1 ratio. LCMS calculated for C16H14BrN2O (M+H)+: m/z=329.0, 331.0. found: 329.0, 331.0.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO.N1CCCCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:18]([NH2:20])=[O:19])=[C:2]([N:1]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1

Procedure:
5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(tert-butyl)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.