Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:30]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:30])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(N3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (18 mg, 0.044 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(pyrrolidin-1-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (12 mg, 0.032 mmol, 72.1% yield). 1H NMR (300 MHz, CDCl3) δ 12.03 (s, 1H); 9.30 (s, 1H); 8.48 (s, 1H); 8.15 (dd, J=8.92, 2.48 Hz, 1H); 6.76 (d, J=9.06 Hz, 1H); 5.24 (s, 2H); 3.95 (s, 3H); 3.66 (dd, J=5.85, 4.09 Hz, 4H); 2.49 (s, 3H); 2.00 (t, J=6.43 Hz, 4H). m/z (ESI, +ve ion) 380.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[S:51]([NH2:55])([NH2:54])(=[O:53])=[O:52].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH:54][S:51](=[O:53])(=[O:52])[NH2:55])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)NS(N)(=O)=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 158 mg (0.293 mmol) of N-(4-iso-propylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acid form of the product of Example 58) and 71 mg (0.440 mmol) of 1,1'-carbonyldiimidazole in 1 mL of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 mmol) of sulfamide and 110 μL (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600E HPLC system with a 4.6×250 mm 5 μM Zorbax-RX C8 at 40° C. and eluting isocratically 1.5 mL/min using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector. After 2.0 hour of additional refluxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diluted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 5500 HPLC by applying the compound in a 4.5 mL total volume (2.5 mL methanol and 2 mL water) onto two in series 21.2×250 mm Zorbax ODS C18 columns and eluting at 15 mL/min with 60% acetonitrile and 40% water both with 0.1% TFA. The column effluent was monitored 254 nM with a Kratos Spectroflow 783 UV detector. Combination and evaporation of the purified fractions afforded 50 mg (28%) of the title compound. The mixed fractions were combined and subjected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65% water and 35% acetonitrile both with 0.1% TFA to 65% acetonitrile and 35% water both with 0.1% TFA, holding all other conditions from the previous chromatography. The purified fractions were combined and concentrated to afford 57 mg (31%) of the title compound, which was combined with the previously purified material to provide a total of 107 mg (59%) of the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[CH:15]=[CH:14]3)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[CH:15]=[CH:14]3)=[O:10])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1-n1ccc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc21
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1yl)-3cyanophenyl)acetate (0.043 g, 0.0837 mmol) in DCM (0.5 mL) was added TFA (0.50 mL, 6.49 mmol). The reaction mixture was stirred for 1 hour and then concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0.5% methanol/DCM with 0.5% AcOH to 5% methanol/DCM containing 0.5% AcOH to provide 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1yl)-3-cyanophenyl)acetic acid as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56 (d, J=3.0 Hz, 1H), 7.24-7.34 (m, 5H), 6.84 (d, J=3.9 Hz, 1H), 3.83 (s, 2H), 3.62 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), MS(APCI)=458.1(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[N:15]([O-])=O.[Na+].[Sn](Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.Cl>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:2]([NH:1][NH2:15])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=N[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NN
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3-Amino-N-cyclopropyl-4-methyl-benzamide (52 mg, 0.27 mmol) in water (3 ml) at 0° C. was added conc. HCl (3 mL) followed by the addition of sodium nitrite (20 mg, 0.30 mmol). The reaction mixture was stirred at 0° C. for 40 min then a solution of tin(II)chloride (114 mg, 0.61 mmol) in conc. HCl (1 mL) was added and the mixture was stirred for 1 hr then allowed to stand at −20° C. for 20 hr before it was warmed to RT. It was neutralized with Na2CO3 solution and extracted with CH2Cl2 six times. The combined extracts were dried over Na2SO4, concentrated, and the resulting solid was used without further purification. HPLC tR 1.06 min; MS m/z 205.9 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[N:13]=2)=[CH:5][CH:4]=1.N>Br>[N:15]1([CH2:14][C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(-c2nc(Cn3ccnc3)cs2)cc1
Agent: Br
Agent: N
Product: Oc1ccc(-c2nc(Cn3ccnc3)cs2)cc1
Yield: 85.5 %

Procedure:
A solution of 0.54 g (2.0 mmol) 1-[2-(4-methoxy-phenyl)-thiazol-4-ylmethyl]-imidazole in 15 ml 47% aqueous hydrobromic acid was stirred at 70° C. for 4 days. The reaction mixture was poured on ice, made basic with concentrated ammonia and extracted with ethyl acetate to yield 0.44 g (85%) raw 4-[4-(imidazol-1-ylmethyl)-thiazol-2-yl]-phenol as tan crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH2:8]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]2[CH2:24][O:23]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+].[Cl-]>CN(C=O)C>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)=[CH:25][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Reactant: c1cc[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.048 g (1.200 mmol) sodium hydride as 60% dispersion in mineral oil is suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and admixed with 0.077 g (1.15 mmol) pyrrole. Having stirred for one hour, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane (Kuliev et al. Uch. Zap. Azerb. Gos. Univ. Ser. Khim Nauk. 1964, 4, 97; Chem. Abstr. 1966, 65, 640c) in 10 ml absolute DMF is added drop-wise. The mixture is stirred for 19 hours, hydrolyzed with a semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator and washed three times with saturated NaCl solution. Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a red oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)[CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[CH:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:28][CH2:29]3)[CH2:15][N:14]([C:5](=[O:7])[CH3:6])[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: Clc1ccc2c(c1)CCNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Acetic anhydride (35 □l, 0.37 mmol) was added to a solution of the amine of example 22 (120 mg, 0.30 mmol) and triethylamine in dichloromethane (5 ml) and stirred at room temperature for 2 hours. The dichloromethane was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound as a white solid (120 mg).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:5]=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29].S(=O)(=O)(O)[OH:32].N([O-])=O.[Na+]>CS(C)=O.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:9][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([N+:28]([O-:30])=[O:29])=[C:2]([OH:32])[N:7]=1
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(N)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of methyl 2-[4-(6-amino-5-nitro-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (56 g, 134.17 mmol) in dimethyl sulfoxide (DMSO, 400 mL) and water (320 mL), is added sulfuric acid 95-97% (80 mL) dropwise. Then the mixture is cooled to 0° C. To the above mixture a solution of sodium nitrite (18.70 g, 268.35 mmol) in water (80 mL) is added dropwise over 15 min at 0° C. The reaction mixture is stirred for 20 min at that temperature and then the cooling bath is removed and the temperature is allowed to rise to RT. To the reaction mixture is added a 0.8 M aqueous solution of buffered sodium phosphate monobasic (1200 mL, pH=6). A yellow suspension appears. This suspension is stirred at RT for 1 h. The solid is filtered, washed with water, and dried in the oven to afford the title compound as an orange solid (49.5 g, 88%). LC-ES/MS m/z 419 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[CH:14]1([CH2:13][S:10]([C@H:8]2[CH2:7][N:6]([C:17]3[N:18]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:19]=[C:20]([CH3:22])[CH:21]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=417.6 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])c(Nc3ccc(Cl)cc3Cl)c2)OCCO1
Temperature: 200 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (8 g), 2,4-dichloroaniline (10.6 g), cupric oxide (0.8 g) and potassium carbonate (5.4 g) was stirred for 3 hours at 200° C. Ethyl acetate (100 ml) was added to the mixture, stirred and filtered. The filtrate was washed with water, dried and evaporated to dryness. The oil (15.5 g) was purified by column chromatography on silica gel (150 g) eluting with toluene to give an oil of 2-[3-(2,4-dichlorophenylamino)-4-nitrophenyl]-2-methyl-1,3-dioxolane (9.7 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].O>CS(C)=O>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=3)=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Nc1cccc(I)c1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
Temperature: 100 °C
Yield: 45.2 %

Procedure:
Next, a mixture of phenyl (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (30.0 mg, 0.11 mmol) and 3-iodoaniline (25.5 mg, 0.12 mmol) in 0.2 mL of DMSO was heated at 100° C. for 16 hours. After cooled to room temperature, water was added and the product was extracted with ethylacetate. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (20.3 mg, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4](F)[N:3]=1.[CH3:10][O-:11].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Fc1cc(I)cc(F)n1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(I)cc(F)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-difluoro-4-iodopyridine (7.37 g, 30.6 mmol) in tetrahydrofuran (200 ml) cooled to 0° C. was added a 0.5 M solution of sodium methoxide (61.2 ml, 30.6 mm) in methyl alcohol. After 4 h the reaction mixture was warmed to ambient temperature. LRMS indicated incomplete conversion to product and additional 0.5 M sodium methoxide solution in methyl alcohol (6.12 ml, 3.06 mmol) was added. After 1 hour the reaction mixture was quenched with water (50 ml), partially concentrated, diluted with ethyl ether, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to afford 2-fluoro-4-iodo-6-methoxypyridine as a yellow oil which was used without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.19 (s, 1H); 7.16 (d, 1H); 3.78 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1OCc1ccccc1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To 1-(Benzyloxy)-2-methoxy-4-nitrobenzene (26 g, 100 mmol) dissolved in ethanol (500 ml) in a 2 liter one-neck flask was added dropwise under 30 minutes a solution af sodium dithionite in water (500 ml), stirring was continued at ambient temperature for 2 h and after that the reaction mixture was heated at 70–80° C. for approx. 4 h, cooled and alkalized with sodium carbonate. The precipitate was filtered, washed with water and dried. The combined water phases were extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was combined with the filtered precipitate to afford 9.3 g (41% yield) of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:25]=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:25][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Reaction time: 24 h
Yield: 44.8 %

Procedure:
A solution consisting of 2.86 g (8 mmol) N-tert-butoxycarbonyl-O-benzyl-L-tyrosinal and 0.701 mL (8 mmol) morpholine (Aldrich, Milwaukee, Wis.) in 36 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 1.06 g (16 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 100 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using ethyl acetate:hexane, 1:1 as eluant. The A white, waxy solid was recrystallized from 2,2,4-trimethylpentane to give 1.53 g (45%) of [2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethyl]-carbamic acid tert-butyl ester as soft white crystals; mp 98-99° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][CH:13]([C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH3:7])([CH3:6])[CH3:5]>CCOCC.[Cl-].[Zn+2].[Cl-]>[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][CH:13]([CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(Cc1cccc(OCC(C)(C)C)c1)C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OCC(C)(C)C)c1)C(O)c1cccc(Cl)c1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a suspension (60 ml) of zinc chloride (4.75 g, 34.8 mmol) in ether was added sodium borohydride (2.64 g, 69.6 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (2.64 g, 69.6 mmol) in ether (40 ml), and the mixture was stirred at room temperature for 1 hr. The reaction was quenched with 1N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, 3:1) to give ethyl (2RS,3RS)-2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate (5.82 g, 81%) as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14]CC)=[O:13])[C:7]2=[O:17].[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2=[O:17]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (5A) (1200 g, 3.754 mol) was charged into a reaction vessel followed by the addition of 2-popanol (1.200 L) and water (7.200 L) and stirred. Sodium hydroxide (600.6 g, 7.508 mol) and water (1.200 L) were mixed and allowed to cool to room temperature. The resulting mixture was charged into the reaction vessel and then was heated to 80° C. with stirring for 3.5 h to generate a dark, homogenous mixture. After an additional hour, acetic acid (9.599 L of 20% w/v, 31.97 mol) was added via dropping funnel over 45 min. The reaction mixture was cooled with stirring to 22° C. at a rate of 6° C./h. The resulting solid was filtered and washed with water (3 L) to generate a wet cake (1436 g). The filtrate was dried in a vacuum oven with a nitrogen bleed over Drierite® to generate 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B) as a brown solid (1069 g). The 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B) was purified by slurrying in 1.5 L methanol and stirring for 6 h. It was then filtered and dried to furnish 968.8 g of purified 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B).