Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@]1(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 4-(((1R,4R)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified via standard methods to afford the title compound (34.2 mg, 0.074 mmol, 30% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.70 (s, 1H), 8.34-8.32 (m, 1H), 8.13 (s, 1H), 4.70 (t, J=12.0 Hz, 1H), 4.64-4.59 (m, 2H), 4.18-4.15 (m, 1H), 1.81-1.74 (m, 3H), 1.68-1.41 (m, 6H), 1.32-1.30 (s, 3H), 0.92-0.85 (s, 6H). MS (ESI) m/z 462.2 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:8]=1[C:9]([N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[C:8]2[C:7](=[CH:21][CH:20]=1)[CH:12]1[CH2:13][C:14](=[O:17])[CH2:15][CH2:16][N:11]1[C:9]2=[O:10]
Reactant: COc1ccc(Br)c(C(=O)N2C=CC(=O)CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1CCC(=O)CC21
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Butyl lithium (3.1 ml, 0.9 M in hexanes, 2.8 mmol) was added dropwise to a solution of 1-(2-bromo-5-methoxybenzoyl)-2,3dihydro-4-pyridinone (0.75 g, 2.4 mmol) in THF (20 ml) at −78° C. After stirring for 2 h, the reaction was quenched with water, extracted with ethyl acetate, the extract dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (240 mg). MS (+EI) m/z 231 [M+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[OH:31])=[CH:26][CH:25]=1>>[CH3:14][NH:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[O:31][CH2:5][C:19]([F:22])([F:21])[F:20])=[CH:26][CH:25]=2)[N:7]=1)=[O:12]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(OCC)C(OCC(F)(F)F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 36.2 %

Procedure:
The title compound was prepared using the procedure for Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol). The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 13.8 mg of the desired product (yield: 18%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.6 Hz, 3 H), 1.31 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.91-4.08 (m, 4 H), 4.12-4.18 (m, 2 H), 4.95 (d, J=14.8 Hz, 1 H), 7.18 (t, J=7.2 Hz, 1 H), 7.36 (d, J=8.4 Hz, 2 H), 7.49 (dt, J=2.4, 7.6 Hz, 1 H), 7.64 (dd, J=1.6, 7.6 Hz, 1 H), 7.68 (d, J=7.6 Hz, 2 H), 8.35 (s, 1 H), 8.43 (m, 1 H). MS (ES+): m/z 636.14 [MH+]. HPLC: tR=1.59 min (UPLC TOF, polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][S:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:26].C([BH3-])#N.[Na+].Cl>CO.C(=O)(O)[O-].[Na+].C(N(CC)CC)C.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:25]([CH3:24])=[O:26])[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)c1ccccc1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: CN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A solution of (3S)-3-(3,4-dichlorophenyl)-3-[(1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionaldehyde (0.54 g) in methanol (10 mL) was treated with 4-(2-methylsulfinylphenyl)piperidine (0.61 g) and the pH was adjusted to 3 with acetic acid and triethylamine. After treating with sodium cyanoborohydride (189 g) the reaction mixture was stirred at ambient temperature for 16 hours, acidified with 10% hydrochloric acid, stirred for 15 minutes and then diluted with a saturated solution of sodium bicarbonate. Upon extraction with dichloromethane, the organic layer was dried and evaporated to obtain the crude product. This material was purified by chromatography, with 20:1 dichloromethane:methanol as the eluent to give the desired 3-[1-(3,4-dichlorophenyl)-3-(4-(2-methylsulfinylphenyl)piperidino)propyl]-2-methyl-2,3-dihydroisoindol-1-one (0.414 g). This material was transformed into the hydrochloride salt as follows. The material was dissolved in dichloromethane (2 mL) and treated with hydrochloric acid in ether (2 mL). The resulting solution was diluted with anhydrous ether (80 mL), stirred for 4 hours, and the resulting precipitate was collected to afford the title compound (0.35 g); mp 180°-188° C.; MS: m/z=555<M+1); NMR(CD3SOCD3): 2.0 (broad,2), 2.3 (broad,2), 2.7 (s,3), 3.1 (s,3), 3.6 (t,2, J=15), 3.76 (m,1), 4.9 (d,1, J=2.4), 6.8 (d,1, J=7.8), 7.0 (s,1), 7.3-7.98 (m,9). Analysis for C30H32C.HCl.H2O: Calculated: C, 59.07; H, 5.78; N, 4.59; Found: C, 59.06; H, 5.72; N, 4.45.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:18]1([CH2:17][C:16]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH2:13][CH2:14][O:15]1
Reactant: CCOC(=O)CC(C)=O
Reactant: OCCc1csc(-c2ccc(Cl)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C)OCCc2nc(-c3ccc(Cl)cc3)sc21
Reaction time: 20 h

Procedure:
A mixture of the starting material of formula II, 2-(4-chlorophenyl)-4-(β-hydroxyethyl)thiazole (24.0 g, 0.1 mole, described in Example 1), ethyl acetoacetate (19.5 g, 0.15 mole) and p-toluenesulfonic acid hydrate (38.0 g, 0.2 mole) in toluene (1000 ml) is heated at reflux temperature, with water separation, for 20 hr. The mixture is evaporated under reduced pressure and the residue is triturated with petroleum ether. The residue is dissolved in a mixture of aqueous sodium bicarbonate solution and ether. The organic solution is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 6,7-dihydro-4-methyl-2-(4-chlorphenyl)-4H-pyrano[4,3-d]thiazole-4-acetate (IV, R1 = Cl, R2 = CH3, A= COOCH2CH3 and n= 1).
Reaction SMILES: ClC1C=CC(C2C3C(OC)=NC=CC=3C3C(C)=N[O:15][C:12]=3CN=2)=CC=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[C:35]=2[N:36]=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[C:35]3[N:36]=[C:26]([O:15][CH3:12])[CH:27]=[CH:28][C:29]=3[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Reactant: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: COc1ccc2c(n1)C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2

Procedure:
A procedure similar to 6-(4-Chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine (Compound 170) was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 340 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.31 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 7.43 (td, J=2.30, 8.70 Hz, 2H), 7.35 (td, J=2.30, 8.70 Hz, 2H), 4.79 (br. s, 2H), 3.34 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: C1(CC2CCCCN2CC(C2C=CC=C([CH:23]([OH:32])[C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])C=2)C)CCCCC1.C1(CC2CCCCN2CC(C2C=CC=C(Br)C=2)C)CCCCC1.C([Li])CCC>C(OCC)C>[Cl:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:31])[C:24]=1[CH:23]=[O:32]
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(C(O)c2c(Cl)cccc2Cl)c1
Agent: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1c(Cl)cccc1Cl

Procedure:
2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-2,6-dichlorobenzyl)phenyl]propyl}piperidine (yellow oil) prepared by reaction of 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.1 mole of butyl lithium in diethyl ether followed by 19.2 g. (0.11 mole) of 2,6-dichlorobenzaldehyde to give 19.3 g. of product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>C(Cl)Cl.Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH:11][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCOc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Nitro-phenoxy)ethylamine (0.27 g) was dissolved in dry DCM (8.5 ml) and dry pyridine (0.15 ml) and isobutyryl chloride (0.12 ml) were then added. After stirring for 1 h at room temperature, the reaction mixture was then diluted with HCl 3 N (50 ml) and extracted with ethyl acetate (50 ml), then the organic phase was washed with brine (50 ml). The organic layer was separated, dried, filtered and evaporated under vacuum to give a crude product which was crystallized (diethyl ether, 7 ml) to give the title compound (0.11 g) as a yellow solid. m.p. 102-103°.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>C(#N)C.C(=O)([O-])O.[Na+]>[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc(N)c1NCCCO
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
N-Chlorosuccinimide (74.1 g, 555 mmol) was added to a stirred solution of methyl 3-amino-2-[(3-hydroxypropyl)amino]benzoate (81.9 g, 370 mmol) in acetonitrile (1480 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. Additional N-chlorosuccinimide (9.88 g, 74.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-45% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown oil (15.7 g, 60.8 mmol, 16%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: COc1ccnc(CSCCN)c1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: COc1ccnc(CSCCN=C(NC#N)SC)c1
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-4-methoxypyridine (3.15 g) in ethanol (25 cc) was added over 1 hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (2.215 g) in ethanol (30 cc) at 22° and the mixture was allowed to stand overnight at room temperature. Nitrogen was passed through the suspension and the mixture was filtered to give N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea m.p. 91.5°-92.5°. (3.9 g).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+].Cl>CO>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.5 %

Procedure:
A mixture of 240 mg (0.462 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 15 mL of methanol was treated with 0.35 mL of 2 M sodium hydroxide and stirred at ambient temperature for 24 hours. The reaction was then adjusted to pH 2 by the addition of 1 M HCl. The mixture was concentrated and the solids were dried in vacuo to provide 162 mg (69%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-([1,1 ′-biphenyl] -2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a solid. nmr (300 MHz, dmso-d6) δ0.78 (t, 3H), 2.44 (s, 3H), 2.60 (q, 2H), 4.84 (s, 2H), 5.40 (s, 2H), 6.74 (d, 1H), 7.2-7.5 (m, 9H), 7.60 (s, 1H), 7.97 (s, 1H)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH:37]([OH:47])[C:38]2[O:39][C:40]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[N:46]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][CH:33]([CH2:36][C:37]([C:38]2[O:39][C:40]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[N:46]=2)=[O:47])[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)c2nc3cnccc3o2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)c2nc3cnccc3o2)CC1
Reaction time: 16 h

Procedure:
The Dess-Martin periodinane (23.7 mg, 60 μmol) was added to a stirred solution of 4-(2-hydroxy-2-oxazolo[4,5-c]pyridin-2-yl-ethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 7, 19.4 mg, 60 μmol) in anhydrous CH2Cl2 (2 mL). After 16 h, the reaction mixture was diluted with CH2Cl2 (15 mL), before being washed with a saturated aqueous Na2S2O3-saturated aqueous NaHCO3 solution (7:1, 3×5 mL). The CH2Cl2 layer was dried (MgSO4), filtered, and concentrated. Flash chromatography (IH-EtOAc, 1:9) provided the title compound: RT=3.39 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26](C=O)C>C(OCC)(=O)C.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24])#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (143 g, 0.36 mol), Zn(CN)2 (84.7 g, 0.72 mol), Pd(PPh3)4 (20 g, 17 mmol) and dry DMF (1 liter) was stirred under an argon atmosphere at 90° C. for 6 hours. The resulting mixture was, after cooled, diluted with ethyl acetate (1 liter), and washed with aqueous 12% ammonia, water, and saturated brine in order. The organic layer was dried over sodium sulfate, and concentrated, and the residue was treated with methanol, and the resulting insoluble solid was taken out through filtration, and dried under a reduced pressure to obtain tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C@H:15]2[C@@H:10]([CH2:11][CH2:12][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([OH:18])[CH2:14]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2([OH:18])[CH2:12][CH2:11][C@@H:10]3[C@H:15]([CH2:16][CH2:17][NH:8][CH2:9]3)[CH2:14]2)=[CH:24][CH:23]=1
Reactant: OC1(c2ccc(F)cc2)CC[C@H]2CN(Cc3ccccc3)CC[C@@H]2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OC1(c2ccc(F)cc2)CC[C@H]2CNCC[C@@H]2C1

Procedure:
Following the general procedure described in Example 9, Part A, the product of Example 18 (1.0 g, 2.9 mmol), 10% palladium on charcoal (1.0 g), and ammonium formate (2 g) were reacted in methanol (75 mL) to afford the product, a white solid (0.6 g): mp 174°-175° C.; NMR (CDCl3, 300 MHz): 7.5-7.4 (m, 2H), 7.1-6.9 (m, 2H), 3.2-3.0 (m, 2H), 2.8-2.6 (m, 1H), 2.4-2.3 (m, 1H), 2.0-1.0 (m, 25H); MS:249; Anal. Calcd for C15H20FNO.3H2O:C, 70.73, H, 8.23, N, 5.50, F, 7.45; Found: C, 70.82, 70.89, H, 8.10, 8.04, N, 5.14, 5.20, F, 7.08, 6.92.
Reaction SMILES: C[O-].[Na+].[Br:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16]C(=O)C)=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[CH:7]=1>CO>[Br:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[CH:7]=1
Reactant: CC(=O)Oc1ccc2c(CBr)cc(=O)oc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(CBr)c2ccc(O)cc2o1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
NaOMe (5.38 mL, 0.5 M, 2.69 mmol) was added slowly under argon to a stirred solution of 4-bromomethyl-7-acetoxycoumarin 6 (0.80 g, 2.69 mmol) in dry methanol (15 mL). The resulting mixture was stirred for 0.5 h. The methanolic solution was acidified with Dowex 50WX8 (H+) resin, filtered, washed with methanol, and evaporated to afford 7 as a white solid (0.68 g, 100%). TLC (hexane/ethyl acetate, 1:3): Rf=0.58. mp 207° C. 1H NMR (CD3OD, 500 MHz) δ 4.66 (s, 2H, CH2), 6.36 (s, 1H, C═CH), 6.73 (d, J=1.5 Hz, 1H), 6.84 (dd, J=1.5, 8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H). 13C NMR (CD3OD, 125 MHz) δ 27.58, 103.80, 111.17, 112.32, 114.37, 127.54, 153.61, 157.23, 163.24, 163.28. ESIMS calcd for C10H8BrO3 [M+H]+ 255.0. Found 255.1.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C([NH:39][C:40]1C=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[N:39]1[CH:40]=[CH:41][CH:42]=[C:43]([C:46]([N:5]2[CH2:6][CH2:7][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH2:9][CH2:10]2)=[O:51])[CH:44]=1
Reactant: O=C(NCCCOC1CCNCC1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCOC1CCN(C(=O)c2cccnc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting nicotinoyl chloride for acetyl chloride and N-(3-(piperidin-4-yloxy)propyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.51-8.70 (m, 2H) 7.75-7.88 (m, 1H) 7.46 (dd, J=7.73, 4.96 Hz, 1H) 7.20-7.38 (m, 3H) 6.28 (t, J=5.35 Hz, 1H) 4.57 (s, 4H) 3.83-4.01 (m, 1H) 3.40-3.63 (m, 6H) 3.16 (q, J=6.35 Hz, 2H) 1.35-1.95 (m, 7H); MS (ESI(+)) m/e 409 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (3.0 g, 11.9 mmol) in anhydrous CH2Cl2 (120 mL) at 0° C. under a dry N2 atmosphere was treated with triethylamine (3.5 mL, 25.1 mmol) followed by dropwise addition of methanesulfonyl chloride (1.0 mL, 13.1 mmol). After stirring for 2 hours at 0° C., the solution was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to a reduced volume (20 mL). The mixture was diluted with hexanes (100 mL) and allowed to stand at ambient temperature overnight. Colorless crystals were collected by filtration and dried under reduced pressure to provide the title compound (3.60 g, 92%). Rf=0.26 (hexanes:ethyl acetate, 2:1); 1H NMR (CDCl3) δ 7.36-7.18 (m, 5H), 4.71 (br s, 1H), 4.28-4.05 (m, 3H), 2.99-2.81 (m, 2H), 1.40 (s, 9H); MS (APCl+) m/z 254 (M+H)+.