Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([C:7]1([CH3:18])[O:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[S:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:20][CH2:21][CH3:22]>C(O)C.C(OCC)C>[CH2:20]([O:16][C:15](=[O:17])[CH2:14][CH:10]1[S:9][CH2:8][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH3:18])[O:12][C:11]1=[O:13])[CH2:21][CH3:22]
Reactant: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Reactant: CCCBr
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCC1(C)CSC(CC(=O)OCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.41 g of the sodium salt of 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid and 0.63 g of 1-bromopropane are boiled for 1 hour in a mixture of 15 ml of dry ethanol and 5 ml of dry diethyl ether. The mixture is further stirred for 1 hour at room temperature. It is permitted to stand for about 12 hours at 0° and filtered. After distilling off the solvent, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid n-propyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III) triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: CN=C=O
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and methyl isocyanate (0.07 g, 1.2 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.32 g, 1.1 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.22 g, yield: 56.9%). mp: 87-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (s, 3H), 2.88 (d, J=5.0 Hz, 3H), 5.80 (s, 1H), 6.55-6.75 (m, 1H), 7.40 (dd, JHF=2.0 and 9.3 Hz, 1H), 7.56 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1O>>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2F)C1
Yield: 23 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 2-fluoro-4-nitrophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 23%). MS (m/e): 467.4 (M+H+, 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes). The fractions containing the desired product were allowed to stand for 3 d. Some fractions had crashed large crystals (collected 240 mg, pure desired product by 1H NMR). All fractions containing the desired product were collected and concentrated to a yellow solidified foam which was slurried with Et2O (˜40 mL). The white solid that formed was collected by filtration and rinsed with Et2O to yield (1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retention time 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m, 1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44 (m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8]([CH2:11]P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[Si:38]([O:45][C@H:46]1[CH2:50][C@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:48][C@H:47]1[CH:70]=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][S:8](/[CH:11]=[CH:70]/[C@@H:47]1[CH2:48][C@@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:50][C@@H:46]1[O:45][Si:38]([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate (602 mg, 1.45 mmol) was dissolved in THF (50.0 mL) under an atmosphere of argon, a 1.60 M solution of n-butyllithium in hexane (1.81 mL, 2.89 mmol) was added at −50° C., and the resultant mixture was stirred for 1 h. A solution of (1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde (300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and the resulting mixture was stirred for 30 min at room temperature. After quenching by addition of water (200 mL), the mixture was extracted with EtOAc (100 mL×3). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 60% EtOAc in hexane to afford the title compound (84.0 mg, 21%). LC/MS: Rt=1.90 min, ES+ 654 (FA standard).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]=[CH:31][C:30](=O)[CH2:29]1>O1CCCC1.CCCCC>[Cl:7][CH:8]=[C:30]1[CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:28][CH2:29]1
Reactant: O=C1C=Cc2ccccc2OC1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: ClC=C1C=Cc2ccccc2OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
1.1 eq. of n-butyllithium are added to 104 mg (0.3 mmol) of chloromethyltriphenylphosphonium chloride in solution in tetrahydrofuran cooled to 0° C. After stirring for one hour, 40 mg (0.25 mmol) of 1-benzoxepin-3(2H)-one, prepared according to example 25, are added at ambient temperature and the mixture is left for 1 hour. After the usual treatments and evaporating the solvent under reduced pressure, the crude reaction product is taken up in pentane in order to precipitate triphenylphosphine oxide, to give 25 mg (52%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin in the form of two isomers as a Z/E mixture (90/10); 1H NMR (300 MHz, C6D6) 6.98–6.78 (m, 4H), 6.02 (d, J=11.8 Hz, 1H), 5.80 (d, J=11.8 Hz, 1H), 5.68 (s, 1H), 4.65 (4.06) (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22]([Cl:24])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]I.[H-].[Na+]>CN(C=O)C>[CH3:25][N:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[N:9]=[CH:10]2)[C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[CH:20][N:19]=1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc2c(cnn2Cc2ccccc2)c1)c1ncnc(Cl)n1
Temperature: 0 °C
Reaction time: 4.25 h

Procedure:
To (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine (473 mg, 1.40 mmol) in DMF (7.5 ml) at 0° C. was added MeI (0.262 mL, 4.21 mmol), followed by NaH (60% dispersion in oil)(67.4 mg, 1.69 mmol). The resulting mixture was stirred at 0° C. for 4.25 h. An additional 10 mg NaH was added after 3.1 h as TLC indicated remaining starting material. At this point, the reaction mixture was quenched with sat'd aq NH4Cl and diluted with water and EtOAc. The organic layer was washed with water and brine. The aqueous layer and washings were extracted once with EtOAc. The combined organics were dried, concentrated and purified by chromatography (SiO2, elution with 1:1 EtOAc-hexanes) to give N-methyl-(1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine as a pale oil: MS m/z=351 [M+H]+. Calc'd for C18H15ClN6: 350.10.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]Br.CCOCC>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1)#[N:5]
Reactant: BrCc1ccco1
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1ccco1
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (105, 0.32 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.60 mL, 0.32 mmol) at room temperature. Reaction control by TLC showed full conversion after 7.5 hrs. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 57% yield (54 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][OH:24])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Ag]=O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][O:24][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:32])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: COC(=O)c1c(C=NO)cccc1Oc1nc(OC)cc(OC)n1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)ON=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 27 %

Procedure:
2.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-hydroxyiminomethylbenzoate, 3 ml of ethyl 2-bromopropionate and 0.9 g of silver oxide (I) were place in a 50 ml eggplant type flask, and were allowed to stand for one night at room temperature. 10 ml of acetone and 10 g of silica gel were added to the resultant reaction liquor, and the acetone was distilled off under reduced pressure. The resultant product was purified by column chromatography to obtain 0.7 g of the aimed compound (refractive index=1.5261) at a yield of 27%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([CH2:19][C:20]([NH2:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]1([C@H:9]2[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:10](=[O:11])[NH:12][C:10]2=[O:11])[C:13]2=[C:18]3[C:17](=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:2][CH2:3][N:22]3[CH:20]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccccc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-phenyl-pyrrolidine-2,5-dione was prepared according to the Example 40 replacing 2-chloro-4-fluorophenylacetamide with phenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.511 (s, 1H), 7.24-7.36 (m, 6H), 7.13 (d, 1H, J=7.2), 6.8-6.88 (m, 2H), 4.49 (d, 1H, J=8.0 Hz), 4.3 (d, 1H, J=7.6 Hz), 4.08 (m, 2H), 2.88 (m, 2H), 2.088 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([OH:30])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(C)(C)C.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCC(O[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NCCCCC(O[PH](=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
An acetonitrile (29.7 ml) solution of the benzyl 6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate (2.97 g) obtained in the above step (a) was added with benzyl alcohol (3.53 ml) and a pyridine (11.9 ml)-acetonitrile (11.9 ml) mixed solution of pivaloyl chloride (4.20 ml), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction system, and the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and pyridine was removed by azeotropic distillation using toluene. The residue was roughly purified by silica gel (Kanto Kagaku Co., 60 N, spherical, neutral) chromatography (300 g, hexane:ethyl acetate=3:2) to obtain crude benzyl 6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (245 g, 68%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [N:1]1C=CC=C(OC2C=C(C=C(C#N)C=2)N)C=1.N1C=CC=CC=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:1])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#Cc1cc(N)cc(Oc2cccnc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccc(F)cc1

Procedure:
To a solution of 1 eq. (0.1 g, 0.473 mmol) of 3-(pyridin-3-yloxy)-5-cyano-aniline in 0.47 M in CH2Cl2 (1 mL) and 1.6 eq. of pyridine (0.56 g, 0.71 mmol) was added 3 eq. of 4-fluorobenzoyl chloride (0.225 g, 1.42 mmol) and the resultant mixture stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with sat. NaHCO3, dried (Na2SO4) and concentrated in vacuo. The resultant residue was diluted with toluene and concentrated in vacuo (5 times). Purification by chromatography over silica with 5% MeOH/CH2Cl2 as the eluant afforded 134 mg of a the desired title compound of Formula I, N-[3-cyano-5-(pyridin-3-yloxy)-phenyl]]-4-fluoro-benzamide, as a solid (85% yield). Mpt 169-172° C. MS (M−1) 332.3.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1>O1CCOCC1.C(Cl)Cl>[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4M HCl in dioxane (2 mL) was added into a solution of (R)-tert-butyl 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (8 mg, 0.02 mmol) in CH2Cl2 (5 mL). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated, and the crude material was recovered to afford the product 1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((R)-pyrrolidin-2-yl)spiro[indoline-3,4′-piperidine] (3 mg, 47% yield) as a solid. 1H NMR (d6-DMSO, 400 MHz) δ 8.80 (s, 1H), 8.00-8.10 (m, 1H), 7.52 (t, 1H), 7.40 (d, 1H), 5.35-5.45 (m, 1H), 4.60-4.70 (m, 1H), 4.20-4.30 (m, 1H), 3.85-4.00 (m, 1H), 3.70-3.80 (m, 1H), 3.60-3.70 (m, 3H), 3.50-3.60 (m, 2H), 3.20-3.30 (m, 2H), 3.10-3.20 (m, 1H), 2.80-2.90 (m, 1H), 2.50-2.70 (m, 2H), 2.40-2.50 (m, 1H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 2H), 1.90-2.05 (m, 2H), 1.10 (d, 311). MS (APCI+) [M+H]+ 390.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[F:17])=[C:5]([OH:20])[CH:4]=1)[CH3:2].[C:21]([NH:28][CH2:29][C:30](O)=[O:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][C:30](=[O:31])[CH2:29][NH:28][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[C:9]([F:17])[CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (0.37 mmol; 100 mg) in dry THF (2 mL) cooled to 0° C. were added, N-Boc-glycine (0.37 mmol; 64 mg), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro phosphate (0.37 mmol; 190 mg) and triethylamine (1.09 mmol; 153 μL). The reaction was stirred at 0° C. for 3 hours and overnight at room temperature. The mixture was concentrated, treated with saturated NH4Cl and extracted with dichloromethane. Combined organic phases were washed with water, dried over Na2SO4 and concentrated in vacuo. The title compound (91 mg; 58%) was obtained as clear oil after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: N#Cc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A dimethoxyethane (5 ml) suspension of sodium 4-chlorobenzenesulfinate (218 mg, 1.10 mmol) and 2-bromomethylbenzonitrile (215 mg, 1.10 mmol) was stirred at 70° C. for 17 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a short silica gel column and the fraction obtained from the ether eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure to give a white solid. The resulting white solid was washed with ether, and collected by filtration, whereby the title compound (226 mg, 70%) was obtained as a white powder.