Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1ccc([N+](=O)[O-])n1
Yield: 66.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared as in Example 15, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (37 mg, 0.93 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture stirred for an additional 10 min, the 1-bromo-propane (91 μL, 1.00 mmol) was added. The mixture continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-propyl-1H-pyrazole (92 mg, 67%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J=7.6 Hz), 1.90 (2H, sextet, J=7.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=2.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:16](I)=[C:15]([CH3:18])[O:14][N:13]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:12]([CH3:11])=[N:13][O:14][C:15]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1noc(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A mixture of 4-bromophenylboronic acid (1 g, 5 mmol), 3,5-dimethyl-4-iodoisoxazole (0.93 g, 4.2 mmol), bis(triphenylphospine)palladium(II) chloride (59 mg, 2 mol %), NaHCO3 (1.06 g, 12.6 mmol) in DME (5 mL) and H2O (5 mL) was heated to 80° C. under N2 for 18 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a white solid (0.9 g, 86%). 1H NMR (CDCl3): δ 2.26 (s, 3H), 2.40 (s, 3H), 7.13 (d, 2H, J=8.3 Hz), 7.58 (d, 2H, J=8.3 Hz).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1([C:14](=[O:16])[CH3:15])[CH2:13][CH:12]=[CH:11][CH2:10]1>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:14]([CH:9]1[CH2:13][CH:12]2[CH:11]([CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(=O)C1CC=CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CC(C(C)=O)CC21
Reaction time: 11 h

Procedure:
A solution of ethyl diazoacetate (0.266 mL, 2.179 mmol) in dichloromethane (6 mL) was added over 6 hours via syringe pump to a solution of 1-(cyclopent-3-en-1-yl)ethanone (200 mg, 1.816 mmol) and rhodium(II) acetate dimer (16.1 mg, 0.036 mmol) in dichloromethane (6 mL). After an additional 11 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford ethyl 3-acetylbicyclo[3.1.0]hexane-6-carboxylate. MS ESI calc'd. for C11H17O3 [M+H]+ 197. found 197.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=[CH:23][CH2:24][C@@H:25]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][C:36]=1[S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH2:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClC(Cl)C.C(Cl)Cl>[P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C@@H:25]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41](=[O:42])(=[O:43])[NH2:44])=[CH:37][C:36]=2[S:45]([C:48]([F:50])([F:49])[F:51])(=[O:47])=[O:46])[CH2:26][S:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:21]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCN1CCNCC1)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A solution of di-tert-butyl 2-(piperazin-1-yl)ethyl phosphate (INTERMEDIATE 60, 0.31 g, 0.95 mmol) in 1,2-dichloroethane (4 ml) was added to a solution of (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 0.46 g, 0.95 mmol) in dichloroethane (5.0 ml) at room temperature. The reaction mixture was allowed to stir for 15 minutes at r.t, and solid sodium triacetoxyborohydride (0.30 g, 1.43 mmol) was added. The mixture was stirred for 1 hour at ambient temperature. To the reaction mixture was added 0.5 N NaOH (10 ml) and DCM (20 ml). After stirring for 15 mins at r.t, the layers were separated and the organic layer was washed with NaHCO3 (saturated aq.) and brine, and dried (Na2SO4). The volatiles were removed under reduced pressure. Purification by column chromatography (ISCO, silica gel, eluting with 0→100% EtOAc/hexanes) gave the title compound (0.71 g, yield: 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)CC>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Solvent: CCCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([OH:17])=O)[C:11]=3[CH:18]=2)=[N:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:17])[C:11]=3[CH:18]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3occ(C(=O)O)c3c2)o1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(C(=O)N4CCOCC4)c3c2)o1
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a suspension of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carboxylic acid (97.7 mg, 0.400 mmol) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (5 mL) was added oxalyl chloride (0.0698 mL, 0.800 mmol) at room temperature, and the resulting mixture was stirred for 15 min. The reaction mixture was added dropwise to a mixture of morpholine (0.105 mL, 1.20 mmol) and saturated aqueous sodium hydrogen carbonate solution (5 mL) at room temperature, and the resulting mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from methanol/water to give the title compound (33.8 mg, yield 27%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([NH:4][C:5]([S:28][CH3:29])=[N:6]3)=[C:2]([NH2:1])[N:10]=2)=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.4 %

Procedure:
100 mg (0.255 mmol) of the compound from example 28 were dissolved in 5 ml of dimethylformamide, and 49 mg (0.357 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 18 μl (0.291 mmol) of iodomethane were added and the mixture was stirred at RT for 48 h. The mixture was concentrated and the residue was taken up in water and acidified with acetic acid. A solid precipitates out, which was filtered off and washed with water. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 18 mg of the title compound were obtained (17% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:29])[CH3:28])=[C:22]([O:30][CH3:31])[CH:21]=1)=O>Cl(O)(=O)(=O)=O>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:17]=2[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:25]=[CH:24][C:23]=1[O:26][C:27](=[O:29])[CH3:28]
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: COc1cc(C=O)ccc1OC(C)=O
Reactant: Nc1ncccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(-c2nc3ncccn3c2NC(C)(C)CC(C)(C)C)ccc1OC(C)=O

Procedure:
Compound (28) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml acetic acid 4-formyl-2-methoxy-phenyl ester solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 410.5; found mass 411.3 (ESI-MS)
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:18]([OH:20])=O)[C:9]2[CH:10]=[CH:11][N:12]([CH:15]([CH3:17])[CH3:16])[C:13]=2[CH:14]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:53][CH2:54][C:55]1[C:56](=[O:65])[NH:57][C:58]([CH3:64])=[CH:59][C:60]=1[CH2:61][CH2:62][CH3:63]>CN(C=O)C.O>[CH3:64][C:58]1[NH:57][C:56](=[O:65])[C:55]([CH2:54][NH:53][C:18]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]([CH:15]([CH3:16])[CH3:17])[C:13]=3[CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=2)=[O:20])=[C:60]([CH2:61][CH2:62][CH3:63])[CH:59]=1
Reactant: CC(C)n1ccc2c(C(=O)O)cc(OCCN(C)C)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
To a cooled (0° C.) mixture of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg, 1.37 mmol) in DMF (10 mL) was added EDC.HCl (310 mg, 1.65 mmol) and HOBt.H2O (250 mg, 1.65 mmol). The reaction was stirred for 15 min, then DIPEA (1.2 mL, 6.89 mmol) and 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (240 mg, 1.37 mmol) were added. The reaction was allowed to warm to RT and stirred for 16 h, at which time it was diluted with water (20 mL) and extracted with DCM (2×15 mL). The combined DCM layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 3% MeOH in chloroform and then further purified by preparative HPLC to furnish 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (120 mg, 19%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.92-0.88 (t, 3H), 1.43-1.41 (d, J=6.8 Hz, 6H), 1.56 (m, 2H), 2.12 (s, 3H), 2.22 (s, 6H), 2.55-2.53 (m, 2H), 2.06 (m, 2H), 4.11-4.09 (t, 2H), 4.36-4.34 (d, J=4.8 Hz, 2H), 4.76-4.73 (m, 1H), 5.90 (s, 1H), 6.74-6.73 (d, J=2.8 Hz, 1H), 7.04 (s, 1H), 7.20 (s, 1H), 7.43-7.42 (d, J=3.2 Hz, 1H), 8.10-8.07 (bs, 1H), 11.55 (bs, 1H). LCMS (ES+): m/z=453.23 [M+H].
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1>O>[CH2:2]([O:3][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:1]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of NaOEt in dry EtOH (45 mL, 114.90 mmol) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (7.0 g, 38.30 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and ethanol was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give I-g as brown oil in 96% yield. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 4.52 (s, 2H), 3.56 (q, J=7.0 Hz, 2H), 2.57 (d, J=10.1 Hz, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C(Cl)C1CCC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CCC2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using cyclobutanecarbonyl chloride and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a colourless oil (105 mg, 85%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:35]=[CH:34]3)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl.C([BH3-])#N.[Na+]>CO.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH:9][CH:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([O:30][CH:27]3[CH2:28][CH2:29][CH:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:25][CH2:26]3)[CH:32]=2)[CH:37]=1)[C:42]([F:43])([F:44])[F:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C(=O)C(F)(F)F)ccc3c2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Amino-propionic acid tert-butyl ester (106 mg, 0.727 mmol) was combined with N,N-Diisopropylethylamine (575 uL, 3.30 mmol) and 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethanone (250 mg, 0.66 mmol) in Methylene chloride (4 mL, 60 mmol). 1 M (of Titanium(IV) chloride in Methylene chloride (727 uL, 0.727 mmol) was added and the mixture was stirred at RT for 5 hours. TLC (20% EtOAC/Hex) shows only traces of SM with new lower Rf spot. The reaction was cooled to 0° C. and Sodium cyanoborohydride (208 mg, 3.30 mmol) in methanol (5 mL) was added carefully in two portions (lots of bubbling so remove cap.) The reaction was then diluted with 10 mL DCM and the solids were removed via filtration. pH was adjust to 10 with 1 M NaOH and the reaction was extracted three times with methylene chloride. Organics were combined and dried over MgSO4. Solids were removed via filtration and the crude reaction was absorbed onto silica (1 g) and purified via column chromatography on 12 g SiO2 using a gradient of 0-15% Ethylacetate/hexane to give material that was impure by NMR and LCMS (compound eluted around 1% EtOAc.) Material was repurified on 24 g ISCO gold column using a long gradient of 0-10% EtOAc/Hex over 30 minutes (desired compound was 2nd major peak) to give the title compound as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([F:11])[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(F)cc(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(F)cc(CC#N)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
To a solution of 1-(chloromethyl)-3-fluoro-5-methoxybenzene (2.9 g, 17 mmol) in DMSO (20 mL), a solution of KCN (2.2 g, 34 mmol) and KI (5.6 g, 34 mmol) in H2O (10 mL) was added. The mixture was stirred at 45° C. for 6 h, poured into H2O (20 mL), and extracted with DCM (3×30 mL). The organic phase was washed with brine (2×10 mL), dried over Na2SO4, and concentrated to give 2.62 g of 2-(3-fluoro-5-methoxyphenyl)acetonitrile. 1H NMR (CDCl3): δ 6.62-6.68 (m, 2H), 6.56-6.60 (m, 1H), 3.80 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH2:21]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:4]([OH:25])=[O:3])=[CH:13][CH:14]=1)(=[O:19])=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethyl ester (140 mg, 0.38 mmol in tetrahydrofuran/water/methanol (0.95 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.76 mL, 0.76 mmol). The reaction was stirred at 25° C. for 8 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 chloroform/methanol) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (88.3 mg, 68.4%) as a clear oil: FAB-HRMS m/e calcd for C18H26O4S (M+H)+ 339.1631 found 339.1638.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[O:11]=[CH:12][C:13](OCC)=O.FC1C=C2C(=CC=1F)NC(=O)C=N2.FC1C(F)=CC=C2C=1N=CC(=O)N2>>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([N:9]=[CH:13][C:12](=[O:11])[NH:10]2)=[CH:5][CH:6]=1
Reactant: Nc1ccc(F)c(F)c1N
Reactant: CCOC(=O)C=O
Agent: O=c1cnc2c(F)c(F)ccc2[nH]1
Agent: O=c1cnc2cc(F)c(F)cc2[nH]1
Product: O=c1cnc2ccc(F)c(F)c2[nH]1
Yield: 64.3 %

Procedure:
3,4-Difluorobenzene-1,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate (50 wt % in toluene, 13.0 mL, 63.2 mmol) were reacted as described for Intermediate 152 to give 3.7 g of product as an off white solid, mixture with 30% of the regioisomer 5,6-difluoroquinoxalin-2(1H)-one. The mixture was carried on to the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1.CI.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:33])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1
Reactant: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN(C)CCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 80 °C
Yield: 9.7 %

Procedure:
7-[3-[[(2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (2.2 g, 5.0 mmole) was dissolved in 100 ml of DMF and 700 mg (5.0 mmole) of methyl iodide added, followed by 2.6 g (20 mmole) of diisopropylethylamine. The mixture was heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on 100 g of silica gel using chloroform as eluant and crystallized from isopropanol with addition of 2.5 ml of 4N isopropanolic HCl to give 0.20 g of the title compound as a monohydrochloride, m.p. 176°-178° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=CC(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:14][CH:13]=[C:12]([CH3:17])[CH3:4])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)=CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.093 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in choroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 (s, 3 H) 1.61 (s, 3 H) 3.64 (d, J=6.99 Hz, 2 H) 5.32 (t, J=8.09 Hz, 1 H) 6.65 (s, 1 H) 7.43 (d, J=5.52 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.64 (d, J=8.46 Hz, 1 H) 7.78 (t, J=7.17 Hz, 1 H) 7.92 (d, J=7.72 Hz, 1 H) 8.32 (m, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.