Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1Nc2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
4-Benzyl-N,N-dimethyl-3,4-dihydro-3-oxo-2-quinoxalinecarboxamide (1.47 g) was added and dissolved in ice-cooled trifluoroacetic acid (45 ml), to which was further added triethyl silane (4.6 ml). The reaction mixture was stirred at room temperature for 3 hours, then concentrated. The residue was dissolved in ethyl acetate and washed with 10% aqueous potassium carbonate solution, water and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crystals were washed with IPE to obtain the entitled compound (1.33 g).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([C@@H:21]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[N:22]1[C:28](=[O:39])[CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[CH2:49]([N:55]1[C:59]([CH:60]=[O:61])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:49]([N:55]1[C:59]([C@@H:60]([OH:61])[C@@H:29]([C:28]([N:22]2[C@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25][O:24][C:23]2=[O:27])=[O:39])[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCn1cncc1C=O
Reactant: COC(=O)CC/C=C\CCC(=O)N1C(=O)OCC[C@H]1C(C)C
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCn1cncc1[C@@H](O)[C@H](C/C=C\CCC(=O)OC)C(=O)N1C(=O)OCC[C@H]1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A 1M solution of dibutylboron triflate in dichloromethane (1.56 ml) was added to a solution of the product of step (iv) (422 mg, 1.42 mmol) in dry dichloromethane (9 ml) at 5° C. under argon, followed by diisopropylethylamine (0.295 ml, 1.7 mmol). The reaction mixture was stirred at 5° C. for 30 minutes and then cooled to -78° C. A solution of the product of step (iii) (280 mg, 1.56 mmol) in dichloromethane (2 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes before being allowed to warm to room temperature. The reaction was quenched by the addition of pH7.2 phosphate buffer solution (1.36 ml) followed by hydrogen peroxide (0.4 ml, 30% w/v aqueous solution). The mixture was stirred for 30 minutes and then poured into water and extracted three times with dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give methyl (7S,4Z)-7-[(S)-(1-hexylimidazol-5-yl)hydroxymethyl]-8-[(S)-4-isopropyl-2-oxo-1,3-oxazinan-3-yl]-8-oxo-oct-4-enoate (450 mg, 66% yield) as an oil; NMR 0.8-0.95(9H,m), 1.25-1.4(6H,m), 1.7-1.9(2H,m), 2.1-2.9(8H,m), 3.68(3H,s), 3.85-4.22(4H,m), 4.6-4.72(1H,m), 4.88(1H,m), 5.36-5.6(2H,m), 6.93(1H,s), 7.54(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][C@H:10]2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34]>CO>[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Reactant: CN(C)CCNc1ccccc1S
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1ccc([C@H](Sc2ccccc2NCCN(C)C)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide and xylene is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-(2-dimethylaminoethylamino)thiophenol and ferrous sulfate heptahydrate in methanol is added immediately into the reaction mixture, and the mixture is reacted at the same temperature, and cooled to room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved with heating in ethanol and water. The mixture is allowed to cool to 0° C., and the precipitated crystals are collected by filtration, washed with chilled 50% ethanol, and dried to give (2S,3S)-3-[2-(2-dimethylaminoethylamino)phenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionamide.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH:11]=O.[CH2:13]([O:20][C:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21](=[O:22])[CH:23]=[CH:11][CH2:10][CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: O=CCC1Cc2ccccc2C1
Solvent: ClCCl
Product: O=C(C=CCC1Cc2ccccc2C1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
3.97 g (24.8 mmol) of (indan-2-yl)acetaldehyde was dissolved in 50 ml of methylene chloride, to which was added 12.2 g (29.8 mmol) of benzyloxycarbonylmethylene triphenyl phosphorane and stirred for 1.5 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 6.45 g colorless oil. Yield: 89%
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[O:4][CH:3]=1.[C:14]([NH:17][NH2:18])(=[O:16])[CH3:15]>>[C:14]([NH:17][NH:18][C:11]([C:8]1[CH:9]=[C:10]2[C:2]([Br:1])=[CH:3][O:4][C:5]2=[CH:6][N:7]=1)=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)NN
Reactant: O=C(O)c1cc2c(Br)coc2cn1
Product: CC(=O)NNC(=O)c1cc2c(Br)coc2cn1
Yield: 95 %

Procedure:
In the same manner as in Reference Example 1 and using 3-bromofuro[2,3-c]pyridine-5-carboxylic acid instead of benzothiazole-6-carboxylic acid and acetohydrazide instead of tert-butyl carbazate, the title compound (yield 95%) was obtained as colorless amorphous.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[F:11][CH:12]([F:33])[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15](Cl)[C:14]=1[C:29]([O:31][CH3:32])=[O:30].[Li].N1C=CC=N1>O1CCCC1.O>[F:22][C:19]([F:20])([F:21])[C:17]1[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:14]([C:29]([O:31][CH3:32])=[O:30])=[C:13]([CH:12]([F:11])[F:33])[N:18]=1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1-n1cccn1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
To a solution of 0.94 g (0.014 mol) of pyrazole in 25 ml of anhydrous tetrahydrofuran was added 0.9 g (0.014 mol) of n-butyllithium. This cloudy solution was then transferred to a solution of 5 g (0.014 mol) of product of Example 103 in 25 ml of anhydrous THF. The solution turned red upon addition of the pyrazole lithium salt. After 45 minutes at room temperature the reaction was complete. The mixture was poured into 100 ml of water and extracted with two 75 ml portions of ether. The combined ether layers were washed with two 100 ml portions of water, dried (CaSO4), filtered and concentrated to 4.1 g of oil which was about 80% product. Trituration with petroleum ether gave 2.4 g (45%) of pure product; mp 42°-52° C. Recrystallization from cyclohexane afforded an analytical sample; mp 48.5°-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:37]([NH:36][CH2:34][CH3:35])=[O:38])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCN=C=O
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.018 g, 0.038 mmol) in CH2Cl2 (0.2 mL) at 0° C. was added ethylisocyanate (0.0030 mL, 0.038 mmol). The mixture was stirred from 0° C. to room temperature for 16 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC to give 0.019 g (92%) of 1-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-ethyl-urea as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.6, 2.4 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.7 Hz), 7.18 (s, 1H), 7.15 (t, 1H, J=9.0 Hz), 7.06-6.97 (m, 2H), 4.30 (m, 1H), 3.60-3.40 (m, 10H), 3.20 (m, 4H), 3.05-2.85 (m, 7H), 2.07 (m, 4H), 1.15 (t, 3H, J=7.5 Hz). MS-ESI: 545.0 (M+H+).
Reaction SMILES: [ClH:1].O1CCOCC1.[O:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]1[CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CO>[ClH:1].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH:18]2[CH2:19][NH:20][CH2:21][CH2:22][N:17]2[C:9]2[O:8][C:16]3[C:11]([N:10]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ncccc3o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cncc(OCC2CNCCN2c2nc3ncccc3o2)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(oxazolo[4,5-b]pyridin-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (273 mg, 0.664 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were combined and brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.116 mL) was added. The mixture was concentrated under reduced pressure to give 148 mg (64%) of the desired product as the hydrochloride salt. LC-MS: RT=2.18 min, [M+H]+=312.5.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][O:11][CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[NH2:8][C:6]1[N:7]=[C:2]([NH:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]2[CH2:12][O:11][CH2:10][CH2:9][C:4]=2[N:5]=1
Reactant: CCCCCN
Reactant: Nc1nc(Cl)c2c(n1)CCOC2
Product: CCCCCNc1nc(N)nc2c1COCC2
Yield: 59 %

Procedure:
A mixture of 4-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2-ylamine (29.3 mg, 0.158 mmol) and amylamine (1.0 ml) was refluxed for 2.5 hours. After reaction, the procedure according to pro-treatment of Example 7 was carried out to give the object compound (22.3 mg, 59%).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:12][C:11]2([CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOC(C)=O>[ClH:1].[ClH:1].[CH2:2]([N:9]1[CH2:12][C:11]2([CH2:16][CH2:15][CH2:14][NH:13]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC12CN(Cc1ccccc1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CC3(CCCN3)C2)cc1
Reaction time: 12 h
Yield: 96 %

Procedure:
A 4M solution of HCl in EtOAc (2 L) was added to a solution of tert-butyl 2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate (Intermediate 50, 195 g, 644.8 mmol) in EtOAc (0.5 L) and the mixture was stirred for 12 h. The resulting solid was collected by filtration and washed with tert-butylmethyl ether (2 L) to give the title salt (170 g, 96%) as white solid; 1H NMR: (d4-methanol) 2.04-2.11 (2H, m), 2.41 (2H, t), 3.39 (2H, t), 4.33 (2H, s), 4.81-4.88 (2H, m), 7.49-7.58 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=CC(N)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:39][CH3:38])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: COc1ccc(N)cc1
Product: COc1ccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 4-methoxy-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 35:65 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)=[O:14])=[CH:5]2.[CH3:27][NH:28]CCNC.[C-]#N.[Na+]>C1(C)C=CC=CC=1.[NH4+].[OH-].[Cu]I>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:27]#[N:28])=[CH:11][N:10]=3)=[O:14])=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1nc2ncc(Br)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1nc2ncc(C#N)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 31.7 %

Procedure:
6-Bromo-N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (90 mg, 0.22 mmol), N,N′-dimethylethane-1,2-diamine (24 μl, 0.22 mmol), CuI (4 mg, 0.02 mmol), KI (7 mg, 0.04 mmol) and NaCN (13 mg, 0.26 mmol) were suspended in toluene (2 ml). The mixture was stirred at 120° C. for 48 hours in a closed high-pressure flask. The reaction was cooled, diluted with NH4OH (30 ml) and extracted with CH2Cl2 (3*30 ml). Combined organics were washed with water (30 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using CH2Cl2/CH3OH (25:1) as eluent to give 25 mg (32%) of the title compound as pale solids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6]([CH3:9])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24]C(S)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6][C:9]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: Sc1ccc(Br)cc1
Reactant: COC(=O)C(CS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CSc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Solution of 2-tert-Butoxycarbonylamino-3-methylsulfonylpropanoic acid methyl ester (0.86 g, 2.89 mmol) and 4-bromobenzenthiol (0.56 g, 2.89 mmol) in DMF (10 mL) was cooled to at 0° C. and treated with Cs2CO3 (1.1 g, 3.2 mmol). After stirring at room temperature for 2 h, the reaction was acidified with 5% HCl (15 mL) and diluted with ethyl acetate (25 mL). After separation, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with sat. aq NaCl, dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave the desired product (857 mg, 76%) as a white solid. 1H NMR (CDCl3), δ 7.40 (d, J=9 Hz, 2H), 7.27 (d, J=9, 2H), 5.30 (d, J=7 Hz, 1H), 4.56 (m, 1H), 3.59 (s, 3H), 3.35 (ddd, J=7, 7, 12 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N+:12]([O-])=O)[C:6]([CH2:9][C:10]#N)=[N:7][CH:8]=1.C[CH2:16][OH:17].CCOC(C)=O>[Pd]>[CH3:16][O:17][C:8]1[N:7]=[C:6]2[CH:9]=[CH:10][NH:12][C:5]2=[CH:4][CH:3]=1
Reactant: COc1cnc(CC#N)c([N+](=O)[O-])c1
Reactant: CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]ccc2n1
Reaction time: 6 h
Yield: 95 %

Procedure:
A suspension of (5-methoxy-3-nitro-pyridin-2-yl)-acetonitrile (Maybridge, 986 mg, 5.1 mmol) and Pd/C (10%, 986 mg) in EtOH/EtOAc (95/5, 50 mL) was shaken for 6 hours under H2 (60 PSI) in Parr apparatus. The reaction mixture was then filtered through a celite pad, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated, and the residue was dissolved in EtOAc (50 mL), washed with NaHCO3 (saturated solution, 50 mL), dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc), affording 5-Methoxy-1H-pyrrolo[3,2-b]pyridine as a white solid (720 mg, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:12]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Yield: 161.8 %

Procedure:
A suspension of 3-fluoro-4-nitrophenol (6.28 g, 40 mmol), benzyl bromide (5.00 mL, 42 mmol), and K2CO3 (6.63 g, 48 mmol) in acetone (80 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give 4-(benzyloxy)-2-fluoro-1-nitrobenzene (16.0 g, 92% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][C@@H:9]1[C@H:15]1[O:19][C:18]([CH3:21])([CH3:20])[N:17]([C:22](=[O:24])[CH3:23])[C@H:16]1[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:11][CH2:10][C@@H:9]1[C@H:15]1[O:19][C:18]([CH3:20])([CH3:21])[N:17]([C:22](=[O:24])[CH3:23])[C@H:16]1[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC[C@@H](OCCC(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
Add (2R, 5R)-2-{(4S, 5S)-3-Acetyl-4-[3,5-difluoro-benzyl]-2,2-dimethyl-oxazolidin-5-yl}-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.06 g, 0.13 mmol) in 1.0 mL dimethylformamide to 60% sodium hydride (0.006 g, 0.15 mmol) in 0.5 mL dimethylformamide at room temperature and stir for 15 minutes. Add 1-bromo-3-methylbutane (0.023 mL, 0.19 mmol) and stir at room temperature overnight. Add 60% sodium hydride (0.006 g, 0.15 mmol) and 1-bromo-3-methylbutane (0.023 mL, 0.19 mmol) and stir for 4 h at room temperature. Quench with water and extract with diethyl ether, dry the organic layer over magnesium sulfate and concentrate. Subject the residue to silica gel chromatography, eluting with 100% dichloromethane to 90:10 dichloromethane: ethyl acetate to provide the desired compound (0.05 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]1[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCc2ccccc2C1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 1,2,3,4-tetrahydroisochinoline (commercially available) according to the procedure described for Example A. MS (m/e): 302.1 (MH−, 100%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 58%).