Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([O-])=[O:28])[CH3:24].[Na+].Cl.O1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C=C(CN(C)C)C(=O)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=C(CN(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 8 h

Procedure:
To methyl 2-[(dimethylamino)methyl]prop-2-enoate (314 mg, 2.19 mmol) in tetrahydrofuran (1.4 mL) and water (1.4 mL) was added LiOH (52.5 mg, 2.19 mmol). The solution was stirred at 40° C. for 4 hours, before being frozen and lyophilized to afford sodium 2-[(dimethylamino)methyl]prop-2-enoate which was used as is in the next step as is. To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) in DMF (886 μL) was added sequentially sodium 2-[(dimethylamino)methyl]prop-2-enoate (96 mg, 0.71 mmol), 4 M solution of HCl in dioxane (177 μL, 0.708 mmol), TEA (197 μL, 1.42 mmol), and 1-propanephosphonic acid cyclic anhydride (422 μL, 0.708 mmol) at room temperature. The reaction was stirred overnight before being purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained and the water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H24N5O3 [M+H]+: 394, found 394. 1H NMR (600 MHz, DMSO-D6) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.77 (d, 1H, J=8.21 Hz), 7.42 (t, 1H, J=8.21 Hz), 7.35 (d, 1H, J=7.63 Hz), 6.01 (s, 1H), 5.58 (s, 1H), 3.87 (q, 2H, J=7.04 Hz), 3.23 (s, 2H), 2.24 (s, 6H), 0.86 (t, 3H, J=7.04 Hz).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][CH3:15])[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: COc1ccccc1CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1ccccc1COc1cccc([N+](=O)[O-])c1C#N
Yield: 58 %

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and 2-methoxybenzyl alcohol in 58% yield. 1H NMR (400 MHz, DMSO) δ 3.82 (s, 3H), 5.34 (s, 2H), 6.99 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.46 (d, J=6.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.93-7.87 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([F:10])=[CH:19][CH:18]=2)[C:14]([C:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=2)=[CH:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
Benzoyl chloride (33.3 mg, 0.24 mmol) was added to a solution of 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4b, 49.6 mg, 0.215 mmol), triethylamine (0.15 mL, 1.1 mmol) and DMAP (5 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature prior to quenching with water and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform) yielded 1-benzoyl-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (27.8 mg, 39%, HRMS-FAB+ for C21H20N2OF calculated MH+ : 335.15598; found: 335.15457).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][C:6]#[N:7])[CH3:2].[CH2:11]([O:13]C=O)C.[Na:16]>CCOCC>[Na:16].[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](=[CH:11][OH:13])[C:6]#[N:7])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(CC#N)OCC
Agent: [Na]
Solvent: CCOCC
Product: CCOC(OCC)C(C#N)=CO

Procedure:
A mixture of 40.9 . of cyanacetaldehyde diethylacetal, 26.2 g. of formic acid ethyl ester and 100 ml. of absolute ether are added dropwise with stirring to a suspension of 7.4 g. of powdered sodium in 500 ml. of absolute ether. The mixture is stirred at room temperature until disappearance of the sodium (16 hours). Then, the brown precipitate formed (crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal) is left to settle and the supernatant solution is removed by decantation. The residue is washed by decanting twice with 200 ml. of absolute ether each time. The product is stored at 0° C. under absolute ether, since it changes on drying.
Reaction SMILES: [CH:1]([C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Formyl-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (221 mg, 0.79 mmol) was dissolved in anhydrous MeOH (10 mL) and NaBH4 (89 mg, 2.37 mmol) was added in portions. Gas evolved and the suspension was stirred at room temperature. After 30 min, the crude reaction mixture was poured into H2O and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give crude 2-(hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide, which was used directly in the next reaction.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Li])CCC.Cl>C1COCC1.O>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([B:1]([OH:6])[OH:2])=[C:24]([CH:29]=[CH2:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=Cc1cc(OCc2ccccc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(OCc2ccccc2)ccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 602.9 %

Procedure:
Triisopropyl borate (683 mg, 3.63 mmol) was added to a stirred solution of 4-(benzyloxy)-1-bromo-2-vinylbenzene (1.0 g, 0.346 mmol) in THF (9 mL). The solution was cooled in a CO2/acetone bath. A solution of n-butyllithium (1.45 mL of 2.5M in hexanes, 3.63 mmol) was added dropwise over 5 minutes. The cooling bath was left in place and was allowed to warm to room temperature. The mixture was treated with HCl (5 mL of 1N) and water (5 mL), stirred for 1 hour, and extracted with ethyl acetate (3×15 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to an oil which crystallized from diethyl ether/hexanes to provide colorless crystals of the desired product (530 mg, 57% yield). 1H NMR (300 MHz, CDCl3) δ 5.14 (s, 2H), 5.34 (d, J=12.44 Hz, 1H), 5.68 (d, J=17.57 Hz, 1H), 6.97 (dd, J=8.42, 2.56 Hz, 1H), 7.36 (m, 6H), 7.83 (dd, J=17.57, 10.98 Hz, 1H), 8.16 (d, J=8.42 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Cl.[CH2:14]([O:16]CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:14]=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOCC
Agent: Cl
Product: O=C=Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-trifluoromethylaniline (2.16 g, 9 mmol) was dissolved in 20 mL diethylether and added concentrated hydrochloric acid (37%, 1.5 mL, 18 mmol). Upon stirring for 1 hour at 25° C. the solvent was removed in vacuo and the white solid was stripped with toluene (3×20 mL). Diphosgene (13 mL) was added to the ammonium chloride salt and the mixture was refluxed for 3.5 hours until no solid material precipitated on cooling. Excess diphosgene was removed in vacuo and the clear oil was stripped with toluene (3×20 mL). The obtained isocyanate was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH:20]2[CH2:22][CH:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=32)[N:16]=[C:15]([CH3:23])[N:14]4[CH2:24][CH2:25][CH3:26])[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:33]>>[ClH:33].[CH3:23][C:15]1[N:14]([CH2:24][CH2:25][CH3:26])[C:13]2[C:17](=[CH:18][C:19]3[CH:20]4[CH2:22][CH:10]([C:11]=3[CH:12]=2)[CH2:9][NH:8][CH2:21]4)[N:16]=1
Reactant: CCCn1c(C)nc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCn1c(C)nc2cc3c(cc21)C1CNCC3C1
Temperature: 100 °C
Yield: 34 %

Procedure:
6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (90 mg, 0.253 mmol) was dissolved in 3N HCl ethyl acetate (5 mL) and warmed to 100° C. for ½ hour. The mixture was cooled, concentrated, slurried in ethyl acetate, and filtered to provide a white solid (25 mg, 34%). 1H NMR (400 MHz, DMSO-d6)9.56 (s, NH), 7.91 (s, 1H), 7.83 (br m, NH), 7.74 (s, 1H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H) 1.85 (m, 2H), 0.97 (m, 3H). M.p. 147–150° C.
Reaction SMILES: [O:1]=C1CNC(=O)N1CC([O-])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:19]1[C:23](=[O:24])[C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=S)([O-:14])=[O:13]>Cl.O1CCOCC1>[OH:24][CH:23]1[N:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:20](=[O:1])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:22]1=[O:25]
Reactant: O=C([O-])CN1C(=O)CNC1=O
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)C(O)N(Cc2cccc([N+](=O)[O-])c2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The above-prepared dioxoimidazolidine-3-acetate product of paragraph (2) (3.6 g) was dissolved in a mixed solvent of 4N hydrochloric acid and dioxane and the solution was stirred at room temperature for six hours. The reaction solution was concentrated in vacuo to dryness and then chloroform was added to the residue. The crystals were dislodged from the wall of the reaction flask with a spatula. The solid was collected by filtration, washed with chloroform and dried to give 0.8 g of 5-hydroxy-1-(3-nitrobenzyl)-2,4-dioxoimidazolidine-3-acetic acid [Compound 14] as amorphous crystals. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O>>[Cl:7][CH2:8][C:9]1[N:6]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][CH:11]=1
Reactant: CC(C)C(N)=O
Reactant: O=C(CCl)CCl
Product: CC(C)c1nc(CCl)co1
Yield: 6.2 %

Procedure:
In substantially the same manner as in Reference Example 31, isobutyramide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-isopropyl oxazole as an oily product. The yield was 6.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-])=O.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][NH:1][C:4]1[CH:5]=[C:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)cc2cc(-c3ccccc3)[nH]c12
Reactant: COC(=O)CBr
Product: COC(=O)CNc1cc(Oc2ccccc2)cc2cc(-c3ccccc3)[nH]c12

Procedure:
7-Nitro-5-phenoxy-2-phenyl-1H-indole prepared in Preparation 27 and methyl bromoacetate were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:31][CH:28]([CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CN1CCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) and 3-pyrrolidin-1-yl-propane-1,2-diol (88 mg, 0.6 mmol) in 3.0 mL of THF was added 80 μl of pyridine dropwise at room temperature. Upon addition, the reaction mixture was stirred at room temperature for 20 min., and filtered. The orange solid was then washed with ethyl acetate and hexane sequentially and dried in a vacuum oven overnight to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-pyrrolidin-1-yl-propyl ester as an orange solid. 1HNMR (400 MHz, CDCl3 and 2 drops of DMSO-d6) δ 12.63 (s, br, 1H, NH-1′), 11.77 (s, br, 1H, OH), 7.86-7.88 (m, 1H), 7.51-7.53 (m, 1H), 7.42 (s, 1H, H-vinyl), 7.18-7.25 (m, 2H), 6.06 (d, J=2.3 Hz, 1H, H-4′), 4.65-4.73 (m, 2H), 4.44-4.56 (m, 2H), 3.91-3.93 (m, 1H), 3.33-3.52 (m, 2H), 2.88-3.15 (m, 2H), 2.40 (s, 3H, CH3), 2.36 (s, 3H, CH3), and 2.01-2.32 (m, 4H).
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([N:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[O:34][C:33]3=[O:42])=[CH:28][C:27]=2[F:43])C(OCC2C=CC=CC=2)=O)[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:14][CH:13]([NH:15][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[O:34][C:33]3=[O:42])=[CH:28][C:27]=2[F:43])[CH2:12]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N(C(=O)OCc3ccccc3)C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CNC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 1.11 g of 3-({4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-benzyloxycarbonyl-amino)-azetidine-1-carboxylic acid benzyl ester (1.88 mmol) and 200 mg Pd/c 10% in methanol was stirred under hydrogen for h. The Pd/C was filtered and the filtrate evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOC(C)=O>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([O:14][C:3]2[C:2]([F:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cc(F)c(O)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
Methyl 5-fluoro-4-hydroxy-2-methoxybenzoate from step 4 above was coupled to N-Boc-4-piperidinol using Mitsunobu conditions as given in step 4 of Example 1. Methyl 4-(N-t-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoate was obtained as a gum (TLC Rf = 0.19 (3:7 EtOAc:hexanes); HPLC (method A) retention time= 9.9 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>O.COCCOC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[CH2:16][O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a mixture of 2-amino-5-bromophenol (51.3 g, 273 mmol) and NaHCO3 (68.8 g, 819 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (46.2 g, 409 mmol) at 0° C. and the reaction mixture was stirred at 15° C. for 0.5 h then heated at 80° C. for 18 h. The reaction mixture was cooled to ambient temperature. The precipitate was collected by suction, washed with water and dried in vacuo to give 7-bromo-4H-benzo[1,4]oxazin-3-one (59.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.59 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[C:30](Cl)(=[O:32])[CH3:31].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2)(=[O:32])[CH3:31]
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 56.9 %

Procedure:
A stirred mixture of (3R)-3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (400 mg, 1 mmol) and acetyl chloride (0.1 mL, 1.4 mmol) in tetrahydrofuran (5 mL) was heated to reflux for 2 h. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 20 mL), brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silica Gel, 1.5:1 ethyl acetate:methylene chloride) to give (3R)-3-[7-(acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (0.25 g, 57% yield); mp, 88-90° C.; 1H NMR (CDCl3)˜1.43 (t, J=6.9 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.04 (dd, J=5.5, 16 Hz, 1H, CHH), 3.09 (s, 3H, CH3), 3.52 (dd, J=9.5, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.26 (d, J=17 Hz, 1H, CHH), 4.44 (d, J=17 Hz, 1H, CHH), 5.58 (dd, J=5.5, 9.4 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 6.92-7.01 (m, 3H, Ar), 7.41 (t, J=7.8 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 10.37 (s, 1H, NH); 13C NMR (CDCl3)˜14.65, 24.84, 35.47, 36.16, 37.31, 48.71, 53.54, 55.85, 64.44, 111.35, 112.44, 116.83, 117.40, 117.97, 119.10, 131.72, 132.84, 137.65, 141.53, 148.46, 149.06, 168.98, 169.41, 169.57; Anal Calcd for C24H29N3O5+0.7H2O: C, 63.76; H, 6.78; N, 9.29; H2O, 2.79. Found: C, 63.89; H, 6.64; N, 9.14; H2O, 2.70.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2.O>CN(C=O)C>[Br:8][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([F:9])[CH:11]=1)[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc(F)c2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
NBS (0.62 g, 3.5 mmol) dissolved in DMF (5 mL) was added to a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 3.2 mmol) in DMF (5 mL) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hr before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried over vacuum to afford title compound (0.65 g, 85% yield) as a white solid. MS: 244.1 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1[N:8]([CH3:24])[CH:9]=[C:10]2[C:16]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:14][CH2:13][C:12](=[O:23])[NH:11]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:4][C:9]1[N:8]([CH3:24])[C:7]([CH3:6])=[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH2:13][C:12](=[O:23])[NH:11][C:10]=12
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c2c(cn1C)NC(=O)CN=C2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c2c(c(Cl)n1C)NC(=O)CN=C2c1ccccc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of freshly distilled sulphuryl chloride (4.0 ml) in methylene chloride (40 ml) is added dropwise over a period of 20 minutes to a solution of 3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one (5.0 g) in methylene chloride (80 ml) cooled to -60° C. and maintained under inert atmosphere. The reaction is allowed to proceed at -55° C.±5° C. for one hour, then the reaction mixture is poured into a 5% aqueous solution of NaHCO3 (210 ml) and vigorously stirred for 20 minutes. The organic phase is separated, washed with water, dried and evaporated to dryness under vacuum. The obtained residue is crystallized from ethanol yielding 3.7 g of the compound of the title. M.p. 195° C. with decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2]
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (3.00 g, 10.7 mmol) and 3-fluorobenzyl bromide (2.2 g, 11.8 mmol) by essentially following procedures as described in Example 1 to obtain 1.4 g (34%) of a beige solid. mp: 207-209° C.; MS (ES): m/z 388 (M+1); HPLC: Rt=2.28 min (100%).