Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8]C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCOCC1>[NH2:8][C@H:7]1[CH2:6][CH2:5][CH2:4][N:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCCN(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a round bottom flask was added (S)-tert-butyl 2-oxo-1-phenylpiperidin-3-ylcarbamate (100 mg, 0.344 mmol) and 4 N HCl in dioxane (2.2 mL). The reaction was stirred at rt for 3 hr. The solvent was removed to give (S)-3-amino-1-phenylpiperidin-2-one (70 mg, 0.31 mmol, 90% yield) as an HCl salt. Anal. Calcd. for C11H14N2O m/z 190.2. found: 191.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10](C(N3CCN(C)CC3)=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30](C2CCCN(C3C=CC([N+]([O-])=O)=CC=3)C2)=[O:31])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:30]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:31])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc(N)cc3)C2)CC1
Product: CN1CCN(C(=O)C2CCN(c3ccc(N)cc3)CC2)CC1

Procedure:
[1-(4-Amino-phenyl)-piperidin-4-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in a similar manner as [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 443b after substituting (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-4-yl]-methanone for (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone (250 mg, 98%). LC/MS (E/I+) 303.19 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1.CS(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[N:16][C:15]([O:18][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)[CH2:27][CH2:26]2)=[CH:14][N:13]=1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4F)cn3)CC2)n1

Procedure:
The title compound (0.13 g, 49%) was prepared as a white solid from 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (0.15 g, 0.56 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Steps 1-4, 0.23 g, 0.76 mmol) and K2CO3 (0.16 g, 1.12 mmol) in DMF (6 mL) in a manner similar to Example 152, Step 3. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.33 (d, 1H, J=1.0 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.82 (dd, 1H, Ja=8.2 Hz, Jb=1.7 Hz), 7.76 (dd, 1H, Ja=10.2 Hz, Jb=1.6 Hz), 4.40-4.30 (m, 2H), 4.29 (d, 2H, J=6.3 Hz), 3.25-3.10 (m, 2H), 3.09 (s, 3H), 2.98 (septet, 1H, J=7.0 Hz), 2.20-2.05 (m, 1H), 2.05-1.90 (m, 2H), 1.60-1.40 (m, 2H), 1.32 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 476 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C[O-].[Na+]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (21.0 g, 0.067 mol), 2-hydroxy-4-n-octyloxybenzophenone (22.0 g, 0.067 mol), and p-cumene (80 g) are charged to a reaction flask. The mixture is heated to dissolve, and sodium methoxide (1.0 g, 25% in methanol) is added as catalyst. The solution is heated with agitation under a nitrogen flow at reflux (176°-178° C.) for 24 hours. After cooling to room temperature, the solution is filtered, and the black filtered solid (~1 g) is discarded. The product is then precipitated with methanol. The yellow solid (12.5 g) obtained is vacuum filtered, and identified using thin layer chromatography, with toluene:acetone (1:1 ) as the mobile phase. To remove the yellow color, the solid product is dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 8.2 g of the title compound as an off-white solid, m.p. 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20](OC)=[O:21])=[CH:16][CH:17]=3)[C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1.[BH4-].[Li+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([CH2:20][OH:21])=[CH:16][CH:17]=3)[C:12]=2[NH:24][C:25]([C@H:27]2[CH2:28][CH2:29][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:31][CH2:32]2)=[O:26])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(CO)nc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-5-carboxylate (300 mg) obtained in Example 39 is suspended in tetrahydrofuran (15 ml), and thereto is added lithium borohydride (24 mg) under ice-cooling, and the mixture is stirred at room temperature for 20 hours. To the reaction solution is poured 10% hydrochloric acid under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. The reaction solution is alkalified with saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in diethyl ether-n-hexane and collected by filtration to give the title compound (80 mg).
Reaction SMILES: [N:1]([Sn](CCCC)(CCCC)CCCC)=[N+:2]=[N-:3].[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20]>O1CCOCC1>[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[NH:3][N:2]=[N:1][N:28]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: COC(=O)C1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2nnn[nH]2)CC1
Temperature: 145 °C
Yield: 52.8 %

Procedure:
A mixture of azidotributyltin (1.51 mL, 5.48 mmol), and 4-cyano-cyclohexanecarboxylic acid methyl ester (458 mg, 2.74 mmol) in 1,4 dioxane were sealed in a vial and heated in an oil bath at 145° C. for 4 days. The reaction was concentrated, diluted with aqueous sodium bicarbonate (saturated, 200 mL), washed with ethyl acetate (200 mL), acidified to pH 1 with concentrated HCl, and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, concentrated, and tritrated with mixtures of hexanes and ethyl acetate to give 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid methyl ester (304 mg, 52%) as an off white solid. LCMS calcd for C9H14N4O2 (m/e) 210, obsd 211 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[OH:24][CH:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:10]1
Reactant: O=C(CCN1CCC(Sc2ccc(O)cc2)C1)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: Oc1ccc(SC2CCN(CCC(O)Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
(RS)-4-[3-(4-Hydroxy-phenylsulfanyl)-pyrrolidin-1-yl]-1-phenyl-butan-2-one (200 mg, 0.6 mmol) in MeOH (3 ml) was treated with NaBH4 (33.2 mg, 0.9 mmol). After 15 minutes stirring at room temperature, the reaction mixture was acidified to pH 3 with 1N HCl then adjusted to pH 8 with saturated NaHCO3. The aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (ethylacetate) to provide (3RS, 3RS) and (3RS,3SR)-4-[1-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (187 mg, 93%) as a white foam, MS: m/e=344.3 (M+H+).
Reaction SMILES: CC1(C)[O:37][C@H:5]2[O:6][CH:7]([CH2:15][O:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)/[C:21](=[CH:28]/[C:29]4[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])/[C:20]3=[O:36])=[O:18])[C@@H:8]3[O:12]C(C)(C)[O:10][C@@H:9]3[C@H:4]2[O:3]1>Cl.C1COCC1>[OH:12][C@@H:8]1[C@H:9]([OH:10])[C@@H:4]([OH:3])[CH:5]([OH:37])[O:6][CH:7]1[CH2:15][O:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)/[C:21](=[CH:28]/[C:29]2[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])/[C:20]1=[O:36])=[O:18]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC3O[C@@H]4OC(C)(C)O[C@@H]4[C@H]4OC(C)(C)O[C@@H]34)c3ccccc32)[nH]1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC3OC(O)[C@H](O)[C@@H](O)[C@H]3O)c3ccccc32)[nH]1
Reaction time: 1 h
Yield: 60 %

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (3aR,5aS,8aS,8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethyl ester was dissolved in the mixture of 5.0 mL of 6 N HCl aq. and 20 mL of THF. The resultant mixture was stirred at room temperature for 3 h and 40 C for 1 h and concentrated. The residue was washed with ethyl acetate and THF and dried to give 133 mg (60%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (3R,4S,5R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl ester as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(Cl)(Cl)Cl.C(=O)=O.[Br:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O>ClCCl>[C:2]([O:16][C:14](=[O:15])[C@H:13]([Br:12])[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CC(C)C[C@@H](Br)C(=O)O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Into dichloromethane (80 mL) was condensed isobutene to double the volume (at -50° C. CHCl3 /dry ice). To this solution was added (2R)-2-bromo-4-methylpentanoic acid (28 g, 143.6 mmol) and maintaining the temperature between -400 and -50° C. concentrated sulphuric acid (1 mL) was added dropwise. The reaction was then allowed to warm to room temperature over 20 hours. The solution was then concentrated before adding additional methylene chloride (300 mL) which was subsequently washed with saturated NaHCO3 (2×100 mL) followed by water (2×100 mL). After drying over Na2SO4, the organic layer was filtered and concentrated to give a yellow oil. The material was distilled to give 23 g of (2R)-2-bromo-4-methylpentanoic acid t-butyl ester as a clear colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[NH:7][C@H:8]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]([N:11]1[CH2:16][CH2:15]C[CH2:13][C@H:12]1[C:17](=[O:40])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:29][NH:30][CH:31]=2)=[CH:21][CH:20]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].N(C(OC(C)(C)C)=O)[C@@H](C(O)=[O:57])C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:47])[NH:7][C@H:8]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:57][CH2:13][C@H:12]1[C:17](=[O:40])[NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:27]2[C:28]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:29][NH:30][CH:31]=2)=[CH:23][CH:24]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1

Procedure:
Using the same procedure for the preparation of 27A, reaction of compound 29A with BOC-D-Phg-OH (11A) afforded the title compound 30A, which was purified by silica column chromatography eluting with dichloromethane/ethyl acetate (10/1, 4/1, 3/1) to give pure 30A as a white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.73 (br s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.84 (s, 1H), 7.58 (d, 2H, J=7.5 Hz), 7.44 (m, 5H), 7.21 (d, 1H, J=9.0 Hz), 6.98 (d, 1H, J=8.0 Hz), 5.48 (d, 1H, J=6.0 Hz), 5.40 (d, 1H, J=5.0 Hz), 5.30 (s, 1H), 4.83 (d, 1H, J=12.0 Hz), 3.79 (d, 1H, J=13□0 Hz), 3.66 (t, 1H, J=13.0 Hz), 3.60 (t, 1H, J=1.0 Hz), 3.44 (dd, 1H, J=11.0, 1.5 Hz), 3.08 (t, 1H, J=10.5 Hz), 1.45 (s, 9H). LCMS (ESI) m/z 678.24 (MNa+), 656.25 (MH+), 600.16, 556.17. HPLC: tR=5.12 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N′-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50%) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[CH3:24][C:25]1(C)[O:30]C(=O)[CH2:28][C:27](=O)[O:26]1>C(Cl)Cl.CN(C=O)C.Cl.CCO>[O:10]=[C:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11])[CH2:24][C:25]([O:26][CH2:27][CH3:28])=[O:30]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 2-phenylpropanoic acid (5.0 g, 33.3 mmol) in DCM (50 mL) was added (COCl)2 (8.5 g, 66.7 mmol) and 2 drops of DMF in ice-bath. The reaction mixture was stirred at r.t. for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. To a solution of pyridine (6 mL) in DCM (50 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (5.8 g, 40.0 mmol) and the above residue in ice-bath. The reaction mixture was stirred at r.t. for 2 h. Diluted with 1N HCl (50 mL), extracted with DCM (50 mL×3), washed with brine (50 mL), dried over Na2SO4, filtered, concentrated to give a residue. The residue was dissolved in EtOH (50 mL) and then stirred at reflux for 3 h. Removed solvent, purified by flash column chromatography to give the title compound (3.6 g, 49%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, t, J=7.2 Hz), 1.41 (3H, d, J=7.2 Hz), 3.28 (1H, d, J=15.6 Hz), 3.40 (1H, d, J=15.6 Hz), 3.89-3.91 (1H, m), 4.11-4.14 (2H, m), 7.20-7.22 (2H, m), 7.27-7.36 (3H, m).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:27][C:28]1([F:43])[CH2:33][CH2:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH2:29]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:31]3[CH2:32][CH2:33][C:28]([F:43])([F:27])[CH2:29][CH:30]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCC(F)(F)CC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (WO2010/057121).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10]O)=[NH:6].S(Cl)([Cl:20])=O>O>[CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][Cl:20])=[NH:6]
Reactant: Cc1cccc(C(=N)NOCCO)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: O
Product: Cc1cccc(C(=N)NOCCCl)c1[N+](=O)[O-]

Procedure:
4.75 g (19.9 mmol) of 3-methyl-N-(2-hydroxyethoxy)-2-nitrobenzamidine are stirred at 60° C. in 45 ml (617 mmol) of thionyl chloride for 3 h. The mixture is then cooled and carefully poured into water. The mixture is extracted with methylene chloride, the extracts are dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed on silica gel (cyclohexane:ethyl acetate:=4:1).
Reaction SMILES: C1(O)C=CC=CC=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:31]=[CH:30][C:18]([CH:19]=[C:20]2[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]2=[O:29])=[CH:17][CH:16]=1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:27][C:23]1([CH3:28])[O:24][C:25](=[O:26])[C:20](=[CH:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:16][CH:17]=2)[C:21](=[O:29])[O:22]1
Reactant: C1=COCCC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1

Procedure:
Protection of the phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1977) J. Org. Coed. 42: 3772. Compound 1.1 (500 g, 2 mol) was dissolved in dichloromethane (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture heated to a gentle reflux (3.5 h). HPLC showed ˜90% completion of the reaction. The reaction was concentrated under reduced pressure to ˜2 L of volume. 1 L of acetone was added, and 2 L of solvent was removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50° C. until no further solvent collected in the traps. Compound 52.1 (528 g) was obtained as fine, light yellow crystals. 1H NMR(400 MHz)(DMSO-d6) δ 8.29 (s, 1H); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz); 5.67 (m, 1H); 3.70 (m, 1H); 3.60 (m, 1H). 1.9-1.5 (m, 12H). MS ESI (pos.) m/e: 355.1 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15]COCC>CO>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Reactant: CCOCC
Solvent: CO
Product: COC(=O)c1cc(C)cc([N+](=O)[O-])c1N
Yield: 83 %

Procedure:
To a solution of 2-amino-5-methyl-3-nitro-benzoic acid (5 g, 24 mmol) in a mixture of methanol & ether (8:2, 50 mL), a freshly generated diazomethane gas collected in ether was added until the reaction completes. The reaction mixture was evaporated under reduced pressure and was purified by flash column chromatography using 5% ethyl acetate in hexane as an eluent to get 4.5 g (83%) of the required product as a yellow coloured solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:60][C:61]1[CH:62]=[C:63]([CH2:67][NH2:68])[CH:64]=[CH:65][CH:66]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:63]3[CH:64]=[CH:65][CH:66]=[C:61]([F:60])[CH:62]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCc1cccc(F)c1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2cccc(F)c2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(3-fluorophenyl)methanamine (60 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (201 mg) as a yellow solid. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[N:7]([CH3:20])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH3:2].C(N(CC)CC)C.SCC(O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[NH:7][CH3:20])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CS
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NC)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sulfonamide 16-7 (4.7 gm, 10 mmol) in CH2Cl2 (50 mL) was treated with triethylamine (2.8 mL, 20 mmol) and mercaptoacetic acid (1.04 mL, 15 mmol). The reaction was stirred for 90 min at room temperature. The green solution was diluted with EtOAc (500 mL) and washed with satd aq NaHCO3 (150 mL), water (3×100 mL), and brine (3×100 mL). The solution was dried over Na2SO4, filtered and concentrated to a black oil. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to give the desired product 16-8.