Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].CON(C)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
A solution of 1-bromo-3-chloro-5-fluoro-benzene (31.5 g, 0.15 mol) in anhydrous THF (120 mL) was added dropwise to the Mg (5.4 g, 0.22 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr until most of the magnesium was consumed. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (20.4 g, 0.075 mol) in anhydrous THF (200 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (25 g, 98%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>ClCCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([NH:21][CH2:35][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(N)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(NCc2cccc3ccccc23)ccc1Cl
Yield: 62.1 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{2-chloro-5-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (264 mg) was prepared from (S)-2-(5-amino-2-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (316 mg, 0.77 mmol) and 1-naphthaldehyde (0.231 mL, 1.7 mmol) according to Procedure G, except for the following: the reaction was done in 15 mL DCE and 2 mL THF, two additional equiv. NaBH(OAc)3 were added after 2 h and an adapted work-up. After reaction completion, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:26]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccccc1I
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccccc3I)CC1)O2

Procedure:
Compound 49 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-iodobenzoyl chloride and conditions outlined in procedure N. M.p.=165-166° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.90 (m, 2H), 7.78 (t, 1H), 7.58 (m, 2H), 7.39 (m, 3H), 4.31 (dd, 2H), 3.50 (m, 1H), 3.20 (m, 1H), 3.13 (s, 2H), 2.05 (d, 2H), 1.82 (m, 2H); LCMS: 532 [M+H].
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:26](OCC)=[O:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH2:26][OH:27])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OCc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of Ethyl 4-(4-benzylphenylamino)-6-chloroquinoline-3-carboxylate (1.1 g, 2.6 mmol) in THF (13 mL) was added lithium aluminum hydride 2 M solution in THF (4.0 mL, 8.0 mmol) in portions over 10 min at 0° C. The dark brown reaction mixture was stirred at room temperature for 30 min and then treated with 3 mL of water. The resulting solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 95:5 v/v CH2Cl2: EtOH as solvent to afford title compound (880 mg, 88% yield) as a yellow solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:19](=[O:21])=[O:20]>C1COCC1>[Cl:6][C:7]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([Cl:18])[CH:15]=[CH:16][C:17]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1c(Cl)cccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexane, 16.5 ml) was added to a solution of ethyl 2,6-dichlorobenzoate (6.89 g) in THF while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and poured onto solid carbon dioxide pellets. The mixture was acidified to pH1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of cyclohexane and ether to give 2,4-dichloro-3-ethoxycarbonylbenzoic acid (4.35 g) as a white solid mp 168° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:35]=4[NH:34][CH:33]=[CH:32]5)=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:35]=4[NH:34][CH:33]=[CH:32]5)=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (308 mg, 0.66 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid. The resulting solution was stirred for 2 hours at room temperature. The solution was concentrated to give the crude 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid which was used in next step without further purification. MS: m/z 369 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].O1CCCC1.O.[Li+].[OH-].Cl>CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CCOC(=O)[C@@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@@H]1CC(CN2CCC[C@@H](C(=O)O)C2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of Example 18B (71 mg, 0.13 mmol) in mixture of tetrahydrofuran/H2O (1.0 mL/0.5 mL), LiOH (25 mg, 1.03 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until pH=3 and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (35 mg, 53%). 1H NMR (400 MHz, methanol-d4) δ ppm 7.78 (s, 1H), 7.55-7.52 (m, 1H), 7.42-7.38 (m, 1H), 6.20 (s, 1H), 4.05-3.85 (m, 1H) 3.82-3.70 (m, 2H), 3.63-3.48 (m, 1H), 3.20-2.8 (m, 3H), 2.75-2.55 (m, 3H), 2.50-2.40 (m, 3H), 2.35-2.20 (m, 2H), 2.07-1.89 (m, 2H). MS (APCI) m/z 383 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]=[C:19]([O:29][C@H:30]4[C@H:34]5[O:35][CH2:36][C@@H:37]([OH:38])[C@H:33]5[O:32][CH2:31]4)[N:20](COCC[Si](C)(C)C)[C:15]3=[CH:14][C:13]=2Cl)=[CH:8][CH:7]=1.[C:46]([Zn]C#N)#[N:47]>CC(N(C)C)=O.CN(C=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:6]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]3[N:18]=[C:19]([O:29][C@@H:30]4[CH2:31][O:32][C@@H:33]5[C@H:37]([OH:38])[CH2:36][O:35][C@H:34]45)[NH:20][C:15]3=[CH:14][C:13]=2[C:46]#[N:47])=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: N#C[Zn]C#N
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc2[nH]c(O[C@@H]3CO[C@H]4[C@@H]3OC[C@H]4O)nc2nc1-c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of PdOAc2 (15.48 mg, 0.069 mmol) and 1,1′-bis(di-tert-butylphoshino)ferrocene (32.7 mg, 0.069 mmol) in DMAc (0.25 ml) was treated with sulfuric acid (6.76 mg, 0.069 mmol) and stirred at 80° C. for 30 min. Then a solution of (3R,3aR,6R,6aR)-6-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 8, 40 mg, 0.069 mmol) and dicyanozinc (9.71 mg, 0.083 mmol) in DMAc (0.25 ml) was added to the reaction and the reaction was heated to 120 degrees for 16 h. The residue was diluted with 0.7 ml DMF, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title compound. LC-MS: calculated for C25H20N4O4, 440.15, observed m/e: 441.15 (M+H)+ (RT 0.58/2.00 min).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]1>>[OH:26][CH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:19][CH2:20]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: OCCC1CCNCC1
Product: N#Cc1c(N2CCC(CCO)CC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 491 mg (3.80 mmol) of 2-(4-piperidinyl)ethan-1-ol to give 64 mg (49% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:2]([CH:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1Cl

Procedure:
Part D. A mixture of 2,4-dichloroacetophenone (10.0 g, 52.9 mmol) and dimethylformamide diethyl acetal (10.0 mL, 58.3 mmol) was heated to reflux for 12 hours, then cooled and evaporated under high vacuum. The residual oil was separated by column chromatography (silica gel, 1:1 ethyl acetate-hexane) to afford the product, 1-(2,4-dichlorobenzoyl)-2-(N,N-dimethylamino)ethene, as a viscous oil (12.11 g, 49.6 mmol, 94%). TLC RF 0.05 (20:80 ethyl acetate-hexane). Spectral data: 1H NMR (300 MHz, CDCl3): δ 7.40 (1H, d, J=2.2 Hz), 7.38-7.23 (3H, m), 5.33 (1H, d, J=12.4 Hz), 3.11 (3H, br s), 2.89 (3H, br s). MS (NH3—CI): m/e 249 (1), 248 (10), 247 (8), 246 (64), 245 (16), 244 (100).
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].P([O-])([O-])([O-])=[O:14].[Na+].[Na+].[Na+].[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][CH2:28][CH2:27]2>CC(C)=O.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([OH:14])[CH:25]=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2
Reactant: Cc1cccc2c1NCC2
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(O)cc2cc[nH]c12

Procedure:
Potassium nitrosodisulfonate (46.1 g, 172 mmol) was added to a 0.1 M aqueous solution of sodium phosphate at pH=7 (1 L) at room temperature. 7-Methylindoline (CAS #: 65673-86-1) (10.4 g, 78 mmol) was dissolved in 100 mL of acetone and added to the reaction in one portion at room temperature. After 30 minutes the reaction was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate in heptanes) to provide the title compound. MS (ESI+) m/z 148.08 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(#N)C.C[N:23](N=O)[C:24]([NH:26][N+:27]([O-:29])=[O:28])=N.C(N(CC)CC)C>C(O)(=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:9])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:24]([NH2:23])=[N:26][N+:27]([O-:29])=[O:28])[CH:11]=1)[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(N)c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=N[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A mixture of the compound (145 mg) obtained in Example 2, acetonitrile (10 ml), N-methyl-N′-nitro-N-nitrosoguanidine (85 mg), triethylamine (0.08 ml) and acetic acid (0.03 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 106 mg of the titled compound (yield, 54%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([C:15]#[N:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:16][CH2:15][CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: N#CC1CN(Cc2ccccc2)CCC1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CN(Cc2ccccc2)CCC1O
Temperature: 5 °C

Procedure:
A mixture of 1-benzyl-3-cyano-4-hydroxypiperidine (2.3 g, 10.64 mmole) and lithium aluminum hydride (0.6 g, 15.97 mmole) in dry tetrahydrofuran (50 ml) was refluxed for 2 hr. The reaction mixture was cooled at 5° C. and quenched with water, aqueous NaOH (10%) and filtered. Filtrate was concentrated to dryness to afford crude 3-aminomethyl-1-benzyl-4-hydroxypiperidine. Yield 2.1 g (89.6%) C13H20N2O, m/z 221 (M+1), PMR (CDCl3): 1.1-1.9 (3H, m, H3 & H5), 2.1 (1H, m, H6), 2.82 (2H, m, H2), 3.4-3.96 (3H, m, H6 & CH2NH2), 4.16 (1H, m, H4), 4.84 (2H, s, N—CH2Ar), 7.34 (5H, m, ArH).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:26][CH:25]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: COc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed overnight in 400 ml of toluene containing 3.5 g of morpholine and 3.4 g of 4-methoxybenzaldehyde. At the end of this time, an additional 1.7 g of aldehyde was added and heating was continued for six (6) more hours. The reaction mixture was then concentrated and purified by flash chromatography (CH2Cl2, then 10% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.37 g of analytically pure material, m.p. 160°-162° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][C@@H:17]2[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19]([N:24]3[CH:31]=[C:30]([F:32])[C:28](=[O:29])[NH:27][C:25]3=[O:26])[CH2:18]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:1]([N:27]1[C:28](=[O:29])[C:30]([F:32])=[CH:31][N:24]([C@@H:19]2[O:20][C@H:21]([CH2:22][O:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:17]([O:16][CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:34][CH:33]=3)[CH2:18]2)[C:25]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(Cl)cc3)[C@@H](CO)O2)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A 0.23 ml quantity of benzoyl chloride was added to a solution of 0.25 g of 3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine in pyridine. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off. To the residue were added ethyl acetate and water to separate the ethyl acetate layer. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was subjected to silica gel column chromatography using chloroform as an eluent, giving 0.27 g of the title compound in a yield of 70%.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][C:19]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[N:18]2)=[CH:13][CH:12]=1.CN(C)[CH:38]=[O:39]>CN(C)C1C=CN=CC=1>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][C:19]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH:38]=[O:39])=[O:29])=[N:18]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCN3)cc2-c2ccccn2)cn1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1ccc(-n2nc(C(=O)N3CCCCN3C=O)cc2-c2ccccn2)cn1
Reaction time: 0.33 h
Yield: 30 %

Procedure:
4-Dimethylaminopyridine (0.142 g) and trifluoromethane sulfonic acid anhydrate (0.140 mL) were added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridazine (0.203 g) obtained in Example 162 in N,N-dimethylformamide (4.0 mL) at 0° C., followed by stirring for 20 minutes. The reaction mixture was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (65.5 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1ccc(C)c(C)c1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CC(=O)O)(Cc1ccc(C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 11.6 g (29.5 mmol) tert-butyl 4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoate and 100 mL DCM was combined with 20 mL TFA, the reaction mixture was stirred for 3 h at RT and evaporated down under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)C(O)CC2
Temperature: 35 °C
Yield: 68.8 %

Procedure:
A 3 L one neck flask fit with an overhead stirrer, condenser, nitrogen inlet, solids addition funnel, and thermometer was charged with crude 6-t-butyl-1-indanone (109 g, 0.577 mol) and anhydrous ethanol (1.5 L). The reaction was heated to 30-40° C. and sodium borohydride (43.6 g, 1.15 mol) was added over the course of 30 min followed by heating to reflux overnight. The next day an additional amount of sodium borohydride is added (12.0 g, 0.32 mol) and reflux continued for an hour. The reaction was cooled, quenched in 5% HCl/ice (1 L), extracted into diethyl ether (1 L), and the organic layer washed with water (14×150 mL), and dried over anhydrous sodium sulfate. Rotary evaporation to remove the solvent gave crude 6-t-butyl-1-indanol (64.4 g). Another diethyl ether extraction as above gave an additional amount of crude 6-t-butyl-1-indanol (75.5 g total). 1HNMR (CDCl3, 500 MHz) δ7.46 (s, 1H); 7.32 (dd, JAB=1.5, 8 Hz, 1H); 7.19 (d, JAB=8 Hz, 1H); 5.24 (t, J=6 Hz); 3.01 (m, 1H); 2.78 (p, J=7.5 Hz, 1H); 2.50 (m, 1H); 1.95 (m, 1H); 1.32 (s, 9H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C:27]([CH3:30])=[N:28][N:29]=5)=[CH:23][CH:24]=4)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34]C)[CH:15]=3)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[Cl-].[NH4+]>ClCCl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C:27]([CH3:30])=[N:28][N:29]=5)=[CH:23][CH:24]=4)[CH:19]=3)[O:31][C@@H:32]([CH3:36])[CH2:33][OH:34])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cc(Oc4ncc(C(=O)N5CCC5)cc4Cl)cc(O[C@@H](C)CO)c3)[nH]2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}pyridine (370 mg, 0.706 mmol) synthesized in Example (71b) was dissolved in dichloromethane (10 mL), and boron tribromide (1.0 mol/L dichloromethane solution, 1.10 mL, 1.10 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with dichloromethane (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=1%-3%) to afford the desired compound (205 mg, yield 57%) as a white solid.