Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:23])([F:22])[F:24])[C:15]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:14]2)[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of the compound from Example 104A were reacted with 194 mg (0.74 mmol) of 2-chlorophenylboronic acid. This gave 54 mg (19% of theory) of the target compound of a purity of 98% and 167 mg (49% of theory) of a purity of 83%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.Br[C:26]1[CH:27]=[C:28]2[C:33]3=[C:34]([CH2:36][C:37]([CH3:39])([CH3:38])[N:32]3[CH:31]=[C:30]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:29]2=[O:45])[CH:35]=1.[CH2:46]([OH:49])[C:47]#[CH:48]>C1COCC1.C(NCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I>[OH:49][CH2:46][C:47]#[C:48][C:26]1[CH:27]=[C:28]2[C:33]3=[C:34]([CH2:36][C:37]([CH3:39])([CH3:38])[N:32]3[CH:31]=[C:30]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:29]2=[O:45])[CH:35]=1
Reactant: C#CCO
Reactant: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CC2(C)C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(cc(C#CCO)cc3c1=O)CC2(C)C
Temperature: 22 °C

Procedure:
A solution of palladium acetate (73 mg) and triphenyl phosphine (191 mg) in dry THF (6.0 mL) under nitrogen is cooled to 0° C. A solution of n-butyllithium (1.6 M in hexanes, 444 μL) is added dropwise and after 15 min, the solution is warmed to 22° C. for 15 min. The solution is then canulated into a mixture of ethyl 8-bromo-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 13, 350 mg), copper iodide (84 mg) and propargyl alcohol (75 μL) in diethylamine (6.0 mL). The reaction is warmed to 45° C. for 2 hours. The reaction is filtered, diluted with CH2Cl2 (100 mL), and washed with water. The organic layer is dried (MgSO4), filtered, and concentrated. The crude product is chromatographed over silica gel, eluting with 5% MeOH in CHCl3 and recrystallized from EtOAc to afford 229 mg of the title compound as white crystals. Physical characteristics: M.p. 237° C. (dec); 1H NMR (DMSO-d6) δ8.74, 7.81, 7.60, 5.37, 4.33, 4.23, 3.39, 1.63 (s, 6 H), 1.29 (t, J=7 Hz, 3 H); IR (diffuse reflectance) 2391, 2222, 2058, 1921, 1680, 1637, 1595, 1542, 1510, 1317, 1216, 1186, 1040, 1031, 808 cm−1; MS (EI) m/z 325 (M+). HRMS (FAB) m/z 326.1385 (C19H19NO4+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:7][CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2ccc(CN3CCCN(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)nc4)CC3)cn2)cc(OC)c1OC

Procedure:
5-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (294 mg) and homopiperazine (50 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C[O:2][NH:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:6].CO.[OH-].[Na+]>O>[OH:2][NH:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:6]
Reactant: CONCC(=O)N[C@@H](CCCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCCC[C@H](NC(=O)CNO)C(=O)O

Procedure:
To a magnetically stirred solution of MeO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (1.0 g, 1.47 mmol), methanol (32 ml) and water (16 ml) was added 1M aq. NaOH solution (3 ml) at room temperature. The reaction and product isolation were carried out according to the method described in Example 13.vi to afford HO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (942 mg, 96%) as a colourless foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc2c(c1)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCS2
Yield: 83.3 %

Procedure:
To a solution of 5-hydroxy-2,3-dihydrobenzothiophene (1.53 g, 10.05 mmoles) in 200 mL acetone was added K2CO3 (12.5 g, 90.45 mmoles) with good mechanical stirring. The suspension was warmed and allyl bromide (4.86 g, 40.20 mmoles) was added in one portion. The reaction mixture was then heated to reflux overnight. After cooling, the solids were removed by filtration and the filtrate concentrated. The residue was taken up in 50/50 vol/vol hexane/methylene chloride and refiltered to remove the remaining salts. Concentration afforded 3.2 q crude product (a yellow oil) which was purified by flash chromatography (3% EtOAc in hexane to elute) to give 1.61 g pure product (83.4%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
To a well-stirred mixture of (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 1.21 mmol) and Dess-Martin periodinane (272 mg, 1.21 mmol) in CH2Cl2 (10 mL), slowly wet CH2Cl2 (24 μL of water in 2 mL of CH2Cl2) is added. The clear solution becomes cloudy towards the end of wet CH2Cl2 addition. The mixture is diluted with Et2O and concentrated to a few mL of solvent by rotary evaporation. The residue is taken up in Et2O, and washed with a 1:1 10% Na2S2O3/saturated aqueous solution of NaHCO3, followed by H2O and brine. The aqueous washings are back-extracted with Et2O, and this organic layer is washed with H2O and brine. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.16 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:20]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]C1.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(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][C:17]([N:28]3[CH2:27][CH2:26][N:25]([CH:20]4[CH2:22][CH2:23][CH2:24]4)[CH2:30][CH2:29]3)=[O:19])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCC(CC(=O)O)CC2)cc1
Reactant: C1CCC(N2CCNCC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCC(CC(=O)N3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-acetyl-phenyl)-piperidin-4-yl]-acetic acid (0.11 mmol) in anhydrous DCM (2 mL) is added 1-cyclopentylpiperazine (1.1 eq.), TEA (0.22 mmol), and BOP (0.14 mmol). The resulting mixture is stirred at rt overnight. DCM is evaporated. The residue is dissolved in EtOAc (20 mL), washed with water (5 mL×3) and brine, dried over sodium sulfate, and concentrated. The crude product is purified through PTLC to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (2H, d), 6.85 (2H, d), 3.89 (2H, br), 3.66 (2H, t), 3.49 (2H, t), 2.91 (2H, dt), 2.46˜2.57 (8H, overlapped), 2.26 (2H, d), 2.12 (1H, m), 1.22˜1.95 (12H, m); LC-MS (M+1) 398.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=4[N:24]=3)=[CH:6][CH:7]=2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(O)cc3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(OCC4CC4)cc3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-hydroxyphenyl)[1,3]thiazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([C:13]([OH:15])=[O:14])[CH2:12][O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:17]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([C:13]([O-:15])=[O:14])[CH2:12][O:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:17]
Reactant: O=C(O)C1(CCCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C1(CCCc2ccccc2)CO1

Procedure:
5 g of 2-(3-phenylpropyl)oxirane-2-carboxylic acid is dissolved in the equivalent amount of 1 N sodium hydroxide solution, and the resulting aqueous solution is washed once with diethyl ether and evaporated to dryness. The glassy residue, which is dried at 20° C. in vacuo, consists of the pure sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2(CCC/C=C\c3ccc(Cl)cc3)SC(=O)NC2=O)cc1

Procedure:
A sample of 5-[5-(4-chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-thiazolidine-2,4-dione (Example 103) was hydrogenated in the presence of Lindlars catalyst in ethanol to give the title compound as a white solid, NMR (CDCl3) δ 2.47 (s, 3H), 5.57 (apparent d of triplets, J=7.3, 11.6 Hz, 1H), 6.42 (br d, J=11.6 Hz, 1H) MS m/Z 499.0495 (M+ calcd. for C21H20ClNO4S2 499.0523).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:13]2[N:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)[CH2:17]1)(=[O:32])=[O:31]
Reactant: c1cc2nnc(C3CCCNC3)n2nc1N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC(c2nnc3ccc(N4CCCCC4)nn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution mixture of 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (670 mg), triethylamine (360 mg) and methylene chloride (15 ml), methanesulfonyl chloride (320 mg) was added and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethanol to obtain 3-(1-methanesulfonylpiperidin-3-yl)-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (230 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.O.[OH-].[Na+]>C(O)(=O)C.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
5-bromo-2-methyl-3-nitropyridine (1.808 g, 8.33 mmol) was suspended in glacial acetic acid (16 ml) and water (4 ml) and iron powder (1.411 g, 25.3 mmol) was added in portions over 5 minutes. The reaction was stirred under nitrogen at room temperature for 70 minutes, using a water bath to cool the reaction flask. Then, the reaction was diluted with EtOAc (20 ml) and the suspension was poured into 5 N NaOH (50 ml). The emulsion was filtered through a pad of Celite® (diatomaceous earth), which was washed with water and EtOAc. Layers separated, and the aqueous phase was extracted with EtOAc (2×50 ml). The organic extracts and phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to afford 5-bromo-2-methylpyridin-3-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].C(O)(C)C>C1COCC1.CCCCCC.ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20.00 g (54.51 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene are dissolved in 200 ml of THF and cooled to −78° C. Then 26.16 ml (65.41 mmol) of a 2.5 M solution of n-butyllithium in hexane are added dropwise. The mixture is stirred for 30 min and then 14.43 g (125.37 mmol) of N-formylmorpholine are metered in. After complete conversion is detected (TLC check), solvolysis is carried out at −78° C. with isopropanol. Warming to room temperature is followed by addition of water and extraction twice with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and the solvent is distilled out under reduced pressure. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 5:1). 11.43 g (78% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[CH3:1][NH:2][C:3]1[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])O
Reactant: CNc1ccc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Into a mixture of 17.3 g of N-methyl(5-trifluoromethylpyridin-2-yl)-amine and 100 ml of sulfuric acid was dropped 12.3 g of nitric acid, then, the mixture was stirred for 2 hours while heating at 80° C. After cooling down to room temperature, water was poured into the reaction mixture, and the deposited precipitate was filtrated, then, washed with water, then, dried under reduced pressure to obtain 18.8 g of N-methyl(3-nitro-5-trifluoromethylpyridin-2-yl)-amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[NH:11][CH2:12][C:13]([N:15]([O:18]CC2C=CC=CC=2)[CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[NH:11][CH2:12][C:13]([N:15]([OH:18])[CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCN(OCc1ccccc1)C(=O)CNC(=O)NCc1ccc(N)nc1
Agent: [Pd]
Solvent: CO
Product: CCN(O)C(=O)CNC(=O)NCc1ccc(N)nc1
Yield: 56.3 %

Procedure:
A solution of 98 (38 mg) in MeOH (10 ml) was stirred for 1 h under hydrogen atmosphere in the presence of 10% Pd/C. The resulting mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 181 as white solid (16 mg, 57%). ESI-MS m/z: 268.1 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl.O1CCOCC1>>[CH:1]1([C@@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reaction time: 0.5 h

Procedure:
(S)-N-((R)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.000765 mol), Ethanol (2.7 g, 0.059 mol), and 4.0 M of Hydrogen chloride in Dioxane (2.7 mL, 0.011 mol) are combined and stirred for 30 minutes. The mixture is allowed to stir overnight. The solvent is removed and the residue is dissolved in ethanol. After washing with ethanol 3 more times, the mixture is concentrated and the residue is dried under high vacuum overnight to obtain a solid.
Reaction SMILES: [O-2].[Ca+2:2].[NH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(O)C>[NH2:3][CH2:4][C:5]([O-:7])=[O:6].[Ca+2:2].[NH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: CCO
Product: NCC(=O)[O-]
Reaction time: 5 h
Yield: 99.9 %

Procedure:
5.6 grams (0.1 Mole) of calcium oxide and 15 grams (0.2 Mole) of glycine were placed into a beaker provided with a reflux condenser. 100 ml ethanol was added and the mixture was stirred and boiled at atmospheric pressure for 5 hours. The reaction mixture was then cooled, and thereafter filtered yielding 18.8 grams of calcium glycinate having the physical characteristic of a fine white powder. Approximately 80% of the ethanol solvent was recovered after filtration and may be reused.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([CH:7]([N:14]2[C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(C(F)(F)F)cc21
Agent: Cl
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(C(F)(F)F)cc21

Procedure:
A solution of ethyl 3-phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoate (74 mg, 204 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.07 min, MH+ 335].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][CH:43]([C:46](OCC)=[O:47])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([N:40]3[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cnc(N[C@H]3C[C@@H](CC)N(C(=O)OCC)c4ccc(OC)nc43)nc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCC(CO)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 1 h

Procedure:
To a solution (1.5 ml) of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpiperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg) in tetrahydrofuran is added diisobutylaluminum hydride (1M solution in toluene, 0.486 ml) under ice-cooling, and the mixture is stirred for 1 hour. A saturated aqueous ammonium chloride solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane:ethyl acetate=80:20→70:30) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxymethylpiperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (110. mg). MS (m/z): 697 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[CH2:6][CH2:5]2>Cl.[Pd].C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:7]3[CH2:6][CH2:5][C:4]([CH:3]=1)=[C:8]23
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)N(c1ccccc1C(=O)O)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc2c3c(c1)NC(=O)c1ccccc1N3CC2
Reaction time: 30 h
Yield: 66.6 %

Procedure:
To a solution of 2-(5-methyl-7-nitroindolin-1-yl)benzoic acid (9 g, 0.03 mole), conc. hydrochloric acid (several drops) and ethanol (200 ml) was added 5% palladium-charcoal (1.5 gm). The mixture was shaked under hydrogen (58 psi) for 30 hours. The solvent was removed and the residue was loaded onto a silica gel flash chromatography column (800 g, 230-400 mesh), packed and eluted with dichloromethane (4 l) and 2% methanol in dichloromethane (4 l). The fractions containing product were pooled and evaporated to yield 5 g (66%) of product. Recrystallization from chloroform gave the analytical sample, mp 222°-224° C.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([SH:24])[CH3:23].Cl>C(Cl)Cl>[CH2:22]([S:24][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1)[CH3:23]
Reactant: CCS
Reactant: COc1ccc2c3c([nH]c2c1)CCCCC3C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ccc2c3c([nH]c2c1)CCCCC3C
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
500 mg (1.9 mmol) of the compound obtained in Stage B of Example 1, predissolved in 5 cm3 of methylene chloride distilled over phosphoruspentoxide are added dropwise to a mixture, cooled to 0° C., of 380 mg (2.84 mmol) of aluminum chloride and 2.3 g (37.9 mmol) of ethanethiol. After stirring for 1 h at 0° C., 1.5 eq. of aluminum chloride and 20 eq. of ethanethiol are added again. The mixture is stirred again for 1 h at 0° C. and then poured onto ice, treated with 1N hydrochloric acid and then extracted with dichloromethane. After treatment of the organic phase and purification of the crude product by chromatography on asilica column, the expected compound is obtained.