Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:10])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12
Reactant: NC(=O)c1cnc2sccc2c1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1cnc2sccc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A mixture of 4-chlorothieno[2,3-b]pyridine-5-carboxamide (145 mg, 0.68 mmol) and cyanuric chloride (200 mg, 1.08 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 30 minutes. Ice is added to the reaction mixture and the resultant solids are collected by filtration washing with water to provide 84 mg of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 100–103° C.; 1H NMR (DMSO-d6) δ 7.66 (d, J=6 Hz, 1H), 8.26 (d, J=6 Hz, 1H), 9.03 (s, 1H); MS 195.0 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1([CH2:31][CH3:32])[CH2:9][CH2:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:20][CH2:19]2)=[CH:6][CH2:5]1)[CH3:3]>[Pd].CO>[ClH:1].[CH2:31]([C:4]1([CH2:2][CH3:3])[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH2:20][CH2:19]2)[CH2:6][CH2:5]1)[CH3:32]
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCN(CC3CCOCC3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC1(CC)CCC(c2ccc(OC)cc2N2CCN(CC3CCOCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 99.6 %

Procedure:
Ten percent of palladium on carbon (100 mg, wet) was added to a solution of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine hydrochloride (34 mg) prepared in Example (6g) in methanol (5 mL), and the mixture was stirred for 13 hours under a hydrogen atmosphere at atmospheric pressure and room temperature. The reaction mixture was passed through Celite for filtration, and the filtrate was concentrated under reduced pressure. The residual solid was washed with diethyl ether. It was then filtered to give 34 mg of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15](Cl)=[N:14][C:13]=2[CH:12]=1)(=[O:5])=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:18]4[S:19][C:11]([CH2:10][NH:9][CH2:8][CH2:7][CH2:6][S:3]([N:2]([CH3:27])[CH3:1])(=[O:5])=[O:4])=[CH:12][C:13]=4[N:14]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 385. NMR: CDCl3: 1.99-2.01 (2 H, m, CH2), 2.78-2.81 (2 H, m, CH2), 2.82 (6 H, s, Me), 2.98-3.01 (2 H, m, CH2), 3.84-3.88 (4 H, m, CH2), 4.02-4.05 (4 H, m, CH2), 4.07 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 516.34
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1.[I-:20].[Na+]>CC(C)=O>[CH:15]1([CH2:14][CH2:13][CH2:12][I:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=S(=O)(OCCCC1CCCC1)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a solution of 3-cyclopentylpropyl 4-bromobenzenesulfonate (Preparation 12, 1.0 g, 2.85 mmol) in acetone (30 ml) was added sodium iodide (1.0 g, 6.67 mmol) and the reaction mixture was left to stir at room temperature for 16 h. The resulting precipitate was filtered and the filtrate was diluted with water (100 ml) and extracted with dichloromethane (100 ml). The extract was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a light pink oil (0.60 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)(C)[O:30][CH2:31][CH2:32]O[Si](C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2([CH3:14])[O:30][CH2:31][CH2:32][O:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CC(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccc(OCC3CC3)c(Br)c2)OCCO1
Reaction time: 2 h

Procedure:
A solution of 1-(3-bromo-4-cyclopropylmethoxy-phenyl)-ethanone from example B.b13 (14.0 g; 52.0 mmol) in dry dichloromethane (250 mL) was cooled in an ice-bath before addition of trimethylsilyl trifluoro-methane sulfonate (0.23 g; 1.04 mmol) and dropwise addition of 1,2-bis(trimethylsilyloxy)-ethane (13.15 g; 62.4 mmol). The reaction mixture was stirred for two hours, extracted with 1M aqueous NaHCO3 (100 mL) and dried over MgSO4. The crude is purified by column chromatography on silica gel (ethyl acetate/cyclohexane-9:1) to yield the title compound as pale yellow oil.
Reaction SMILES: NCCC[CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([NH2:9])=O>[Pd].N1C=CC=CC=1>[C:6]([C:7]1[N:9]=[CH:5][CH:6]=[CH:7][N:9]=1)([CH3:5])([CH3:10])[CH3:11]
Reactant: CC(C)(CCCCN)C(N)=O
Agent: [Pd]
Solvent: c1ccncc1
Product: CC(C)(C)c1ncccn1

Procedure:
A pyridine solution of 3-aminopropylpivalamide (approximately 35 percent by weight aminoamide) was fed continuously to a heated 1"×20" reactor maintained at 330° to 345° C. The reactor was packed with 50 g of 0.5 percent palladium on alumina. After removal of pyridine by distillation, the product, 2-t-butylpyrimidine was obtained, b.p. 160° to 163° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][C:13](N2[C@H](C3C=CC=CC=3)[C@H](C)N(C)C2=O)=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:29]1([C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13][OH:14])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C[C@@H](c2ccccc2)c2ccc(S(C)(=O)=O)cc2)C(=O)N1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CCO)c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of (4S,5R)-1-[(S)-3-(4-methanesulfonyl-phenyl)-3-phenyl-propionyl]-3,4-dimethyl-5-phenyl-imidazolidin-2-one (846 mg, 1.78 mmol) in THF (20 mL) at 0° C. was added lithium aluminium hydride (3.6 mL, 1M in THF, 3.6 mmol) and the resulting mixture was stirred for 15 min. The reaction was quenched by the addition of 2M aqueous sodium hydroxide. The phases were separated and the organic phase pre-absorbed onto a Bond Elut and eluted with a gradient of isohexane to ethyl acetate giving the sub-titled compound as a white solid (285 mg, 55%); NMR (CDCl3): 1.63 (br s, 1H), 2.33 (m, 2H), 3.00 (s, 3H), 3.59 (t, 2H), 4.28 (t, 1H), 7.23 (m, 5H), 7.43 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C(=O)=O.CC(C)=O.C[O:17][C:18]([C:20]1([O:23][CH3:24])[CH2:22][CH2:21]1)=O.C(#N)C>C1COCC1>[CH3:24][O:23][C:20]1([C:18](=[O:17])[CH2:2][C:3]#[N:5])[CH2:22][CH2:21]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(OC)CC1
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: COC1(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Add a solution of 2 M LDA in THF (29.1 mL, 58.3 mmol) to a dry ice-acetone cooled solution of 1-methoxy-cyclopropanecarboxylic acid methyl ester (WO2005/014577) (3.45 g, 26.5 mmol) and acetonitrile (2.17 g mL, 53.0 mmol) in THF (30 mL). Stir the reaction mixture at −78° C. for 1 hour and then at 22° C. for 0.5 hour. Evaporate the solvent to give a brown solid. Filter and wash with hexanes. Add 2N hydrochloric acid and extract three times with diethyl ether (50 mL each). Dry the combined organic phases over sodium sulfate. Removal of solvent provides a red oil (3.55 g, 96% yield, ES+(m/z) 140.1 [M+H]).
Reaction SMILES: N[CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6](C=O)[CH2:7][S:8][C@H:3]12.[CH2:16](OP(CC(OCC)=O)(=O)OCC)[CH3:17]>C1COCC1>[CH:16]([CH:7]1[CH:6]=[C:5]([C:11]([OH:13])=[O:12])[N:4]2[C:14](=[O:15])[CH2:2][C@H:3]2[S:8]1)=[CH2:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Solvent: C1CCOC1
Product: C=CC1C=C(C(=O)O)N2C(=O)C[C@H]2S1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 200 mg of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 2 ml of THF is treated at room temperature with 1.08 ml of BSA. The reaction mixture is stirred at room temperature for 10 minutes. A clear solution is obtained containing N,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. The solution is cooled to 0° and treated dropwise with a mixture of 197 mg of diethylethoxycarbonylmethyl-phosphonate and 98 mg of potassium tert.butylate in 2 ml of THF. After 18 hours stirring at 0° the reaction mixture is worked up as described in example 23). 39 mg (15.5%) of 7-amino-3[E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid as a brown coloured powder are thus obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1COCC1>[C:28]1([CH2:34][C:35]([NH:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]4[CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=5)[N:14]=[CH:13][N:12]=4)[C:21]=3[N:22]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
According to the procedure described in Example 67, the title compound was prepared by using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol), phenylacetyl chloride (0.13 mL, 1 mmol, Aldrich), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin) (0.34 g, 0.75 mmol) in THF (5 mL). Purification by silica gel chromatography (1:4 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 507 (M+1). Mp: 188.6–191.0° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[NH:3]1.C1C=CC2N(O)N=[N:26][C:24]=2C=1.C(Cl)CCl.CN>CN(C=O)C>[CH3:24][NH:26][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH2:10][C:2](=[O:1])[NH:3]3)[CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: O=C1Cc2c(cccc2-c2cccc(C(=O)O)c2)N1
Agent: CN
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzoic acid (1.27 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol) and EDC (1.44 g, 7.5 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. To the mixture was added methylamine (2M in THF, 3.75 mL, 7.5 mmol), it was then stirred at room temperature for overnight. Most of the solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO3 (20 mL). The precipitate was collected by filtration, washed with water and dried. The crude product was recrystallized from DCM-hexane to give 1.14 g (86%) of N-methyl-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzamide as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:40][C:39]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:36](=[O:37])[C:35]=1[S:34][CH2:33][CH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.688 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (1.84 g, 11.1 mmol), chlorotrimethylsilane (1.41 mL, 11.1 mmol), THF (111 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 2.95 (t, 2 H), 6.62 (s, 1 H), 6.89 (dd, 2 H), 7.21 (m, 5 H), 7.65 (d, 2 H), 10.22 (s, 1 H), 11.05 (bs, 1 H).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li]CCCC>C1COCC1>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:23])[C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:22])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2ccccc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a pre-cooled (−78° C.) solution of 4,6-dichloro-2-(2-phenyl-propionyl amino)-benzoic acid methyl ester (0.82 g, 2.30 mmol) in dry THF (70 mL) was added dropwise LiHMDS [prepared by treatment of a hexamethyldisilazide (1.47 mL, 6.90 mmol) in dry THF (25 mL) with n-BuLi (3.70 mmol, 2.5M hexane solution) for 1 hour at −78° C.]. The reaction mixture was stirred for 1 hour and then refluxed overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by the addition of 1N HCl aqueous solution. Subsequently, the resultant was extracted with ethyl acetate (150 mL×3), and organic phase was washed with brine (150 mL×2) and water (150 mL×2) dried with magnesium sulfate. After evaporation the solvent, an objective compound (0.57 g, 78%) was obtained as yellow solid by a flash column chromatography (Hexane:EtOAc=4:1): 1H NMR (200 MHz, CD3OD+DMSO-d6) δ 1.61 (s, 3H, CH3), 6.96 (m, 1H, ArH), 7.08-7.34 (m, 6H, ArH); m.p. 222-225° C.; MS(EI) m/e 319 [M+], 285, 132, 104.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15].O>CO>[F:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[C:5]=1[CH2:14][OH:15]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500 ml of methanol was added, with ice-cooling, a solution of 36.8 g (187.6 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 35.4 g (yield: 95.4%) of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:8][C:9]([C:12]([NH:14][C:15]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:21])[C:16]([O:18]CC)=[O:17])=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.O>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1([C:6]2[C:7]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:33])[F:32])=[CH:8][C:9]([C:12]([NH:14][C:15]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:21])[C:16]([OH:18])=[O:17])=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)C(C)(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2(F)COC2)cn1)c1noc(C)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)C(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.2 %

Procedure:
To a solution of ethyl 2-[[5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 183a, 150 mg, 306 μmol) in a mixture of THF (2 ml)/water (1 ml) was added LiOH monohydrate (25.7 mg, 612 μmol). The reaction mixture was sonicated to dissolve the solids. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with 1 mL of an aqueous solution 2M trifluoroacetic acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was dissolved in toluene and evaporated down to dryness to yield to yield the title compound (180 mg, 100%) as a crude solid which was used without any purification. MS (ESI, m/z): 463.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:5][CH:4]=1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CO>[CH:23]1([NH:19][C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=3)[C@@H:10]([CH3:20])[CH2:11]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C

Procedure:
To (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (200 mg, 0.67 mmol) in MeOH was added cyclopentanone (0.073 mL, 0.74 mmol) followed Na(OAc)3BH (284 mg, 1.34 mmol) and catalytic amount of HOAc. The reaction mixture was stirred at room temperature over night. The reaction wash quenched by adding water. And the mixture was extracted with EtOAc 3 times. The organic layers were combined then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine in decent yield.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C:17]#[N:18])=[CH:14]2)=[CH:9][CH:8]=1.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C:17]#[N:18])=[CH:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2ccc(C#N)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2ccc(O)cc2c1
Reaction time: 30 h
Yield: 79.9 %

Procedure:
A solution of BBr3 (840 μL, 8.8 mmol) in CH2Cl2 (4 mL) is added to a solution of 7-methoxy-2-naphthonitrile (646 mg, 3.53 mmol) in CH2Cl2 (6 mL). The reaction is allowed to stir for 30 hours. Water (about 5 mL) is slowly added. The pH is adjusted to 7 with saturated Na2CO3 then the mixture is extracted with CH2Cl2. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness. The crude material is purified by column chromatography (step gradient of 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl12) to give 7-hydroxy-2-naphthonitrile as a white solid (477 mg, 80%). HRMS (EI) calculated for C11H7NO: 169.0528, found 169.0527.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:15][O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[OH:16][CH2:17][C:18](=[CH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:15][O:14][C:8]3([CH2:9][CH2:10][N:11]([CH2:26][CH:18]([CH2:17][OH:16])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:12][CH2:13]3)[C:6]=2[CH:7]=1
Reactant: Fc1ccc2c(c1)C1(CCNCC1)OC2
Reactant: C=C(CO)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C(CO)CN1CCC2(CC1)OCc1ccc(F)cc12

Procedure:
The title compound was prepared according to the procedure described in step 4 of example 4 from 6-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine] (J. Med. Chem. 1995, 38, 2009.) and tert-butyl 2-(hydroxymethyl)acrylate (Synlett 1997, 12, 1417.):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH2:23]([N:30]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[N:10]([O:11][CH:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cnn(Cc4ccccc4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (1-benzyl-1H-pyrazol-4-yl)boronic acid according to the procedure described in example 4.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C)C=C1C(C)=O)C2=O

Procedure:
The title compound 160 is prepared according to the procedure reported in Example 39.1 with compound 121 (500 mg, 1 mmol) and BNAH (214 mg, 1 equiv) as reactants. Yellow solid. (Yield 150 mg, 36%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7][OH:8].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Na+].[Cl-]>C1COCC1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([F:12])=[C:4]([Cl:3])[CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ccc(F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.33 g) was added to a solution of the alcohol from Step 3 (2.0 g) in THF (50 mL) at 0° C. under N2. Stirring was continued for 5 minutes at 0° C. followed by 25 min at 25° C. The mixture was then cooled to 0° C. and p-toluenesulfonyl chloride (2.5 g) was added. Stirring was continued for 40 minutes at 0° C. followed by 2 hours at 25° C. The precipitated NaCl was allowed to settle and the supernatant solution (4.0 mL) of the title compound was used directly in the next step.