Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([NH2:11])[N:5]=1.[CH:12](Br)([CH3:14])[CH3:13].CO>CN(C=O)C>[CH:12]([O:10][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([NH2:11])[CH:7]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Br
Reactant: Nc1cc(O)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(N)nc(N)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
634 mg of sodium hydride (60% in mineral oil, 17.12 mmol) are added in portions under an argon atmosphere to a vigorously stirred solution of 1.8 g (14.27 mmol) of 2,6-diaminopyrimidin-4-ol in 20 ml of DMF. After 30 min, 1.6 ml (17.12 mmol) of isopropyl bromide are added dropwise, and the solution is stirred at 40° C. for 12 h. Methanol (1 mol) is then added to the reaction mixture, which is directly purified by preparative HPLC. Combining the product fractions and removing the solvent result in 250 mg (12% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1.O.C1COCC1>[Cl-].[NH4+].[Zn]>[CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.7 %

Procedure:
To a solution of 4-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-morpholine (1.913 g, 2.88 mmole), in saturated ammonium chloride solution (6 mL), water (6 mL) and THF (12 mL) was added zinc dust (1.123 g, 6 eq) at 0° C. The mixture was stirred at room temp for 1 hour and then filtered off through celite. The solution was dried in vacuo to give title compound as a yellow gummy solid (1.87 g, 99%). Exact mass calculated for C16H22N4O2 302.2. found 303.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16].FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CN1CCN(Cc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (2.51 g, 8.64 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (10 ml). After stirring the mixture at room temperature for 1 hour, the solvent was removed under reduced pressure. The oily residue was crystallized by treating with ethyl acetate and filtered off to give 2-(2-oxo-3-benzylimidazolidinyl)acetic acid (1.56 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>CN1C(=O)CCC1.O>[Cl:27][C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccccc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 300.3 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.134 g, 6.06 mmol) in NMP (10 mL) at 0° C. was added NaH (60%) (202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and 1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The mixture was diluted with water (400 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 25-50% EtOAc in hexane to give the title compound (5.29 g, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=14.16 Hz, 9H), 2.12-2.34 (m, 2H), 3.42-3.58 (m, 3H), 3.69 (td, J=12.33, 4.64 Hz, 1H), 5.63-5.76 (m, 1H), 7.59 (s, 1H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.87-7.92 (m, 1H), 8.11-8.19 (m, 1H); ESI-MS m/z [M+H-tert-butyl]+ 293.5.
Reaction SMILES: [N:1]1([C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:25][C:26]([CH3:28])=O>CC#N>[CH3:25][CH:26]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3]1)[CH3:28]
Reactant: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCNCC3)C2)cn1
Reactant: CC(C)=O
Solvent: CC#N
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C(C)C)CC3)C2)cn1
Yield: 14.2 %

Procedure:
In a similar fashion (Route 1, GP A; except that MeCN was used as solvent), 5-{[1-(1,4-diazepan-1-ylcarbonyl)azetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (25 mg, 0.075 mmol) and acetone (5.5 μl, 0.075 mmol) gave the title compound as colourless oil (4 mg, 14%) after purification by preparative HPLC.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:5]1[CH2:4][CH2:3][CH2:2][C:1]1[O:9][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: O=C(O)CCCC(=O)O
Reactant: Nc1ccccc1O
Product: c1ccc2oc(CCCc3nc4ccccc4o3)nc2c1

Procedure:
1 Mol of glutaric acid is reacted with 2 mols of aminophenol to produce 1,3-bis-(bezoxazole-2-yl)-propane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:38](O)=[O:39])[CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[NH2:41][C@H:42]([CH2:46][OH:47])[CH:43]([CH3:45])[CH3:44]>>[OH:47][CH2:46][C@@H:42]([NH:41][C:38]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:39])[CH:43]([CH3:45])[CH3:44]
Reactant: O=C(O)c1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@@H](CO)NC(=O)c1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1

Procedure:
By treating 200 mg of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic acid obtained by Example 126 and 94.5 μl L-valinol in accordance with Example 127, 102 mg of the title compound was obtained as white crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:6]=2)[CH2:2]1.ClCCl.C(N(C(C)C)C(C)C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CN(C1C=CN=CC=1)C>[F:16][C:13]1([F:17])[CH2:14][CH2:15][N:11]([C:9]2[CH:10]=[C:5]([CH:3]3[CH2:2][N:1]([C:41](=[O:43])[CH3:42])[CH2:4]3)[CH:6]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[N:8]=2)[CH2:12]1
Reactant: CC(=O)OC(C)=O
Reactant: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a solution of 4-(azetidin-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (1-d, 180 mg, 0.4507 mmol) and DMAP (5.6 mg, 0.1 equiv., 0.04507 mmol) in dichloromethane (2 mL, 31.0 mmol) and N-ethyldiisopropylamine (0.47 mL, 6.0 equiv., 2.704 mmol) was added acetic anhydride (0.22 mL, 5.0 equiv., 2.253 mmol), and the brown solution was stirred at 25° C. for 2 h. DCM was removed, and the crude was submitted for HPLC purification to yield 9.5 mg (4.8%) off-white powder. 1H NMR (400 MHz, DMSO) δ (delta) 9.99-9.83 (s, 1H), 8.74-8.62 (s, 1H), 8.48-8.40 (d, J=5.1 Hz, 1H), 7.21-7.11 (d, J=5.2 Hz, 1H), 6.66-6.55 (s, 1H), 6.15-5.96 (s, 1H), 4.53-4.39 (t, J=8.6 Hz, 1H), 4.27-4.15 (t, J=9.2 Hz, 1H), 4.14-4.07 (dd, J=8.3, 6.1 Hz, 1H), 3.94-3.78 (m, 3H), 3.77-3.61 (m, 3H), 2.64-2.52 (dt, J=14.1, 7.0 Hz, 2H), 1.85-1.75 (s, 3H). LCMS: m/z 442 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 64.3 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (211 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (151 mg), a white solid, in 64% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH:30]2[CH2:32][CH2:31]2)[C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:30]1([N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)[CH2:11][CH2:12]2)[C:17](=[O:29])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (5.20 mL) is added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (266 mg) and N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (600 mg) in ethyl acetate (25 mL). The reaction mixture is stirred at 50° C. for 3 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 2 h in a mixture of ethanol (10 mL) and glacial acetic acid (5 mL). The solvents are evaporated and the residue is chromatographed on silica gel [ethyl acetate/cyclohexane/methanol 9:9:2] to give the title compound. LC (method 6): tR=1.66 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of N-tert-butoxycarbonyl-D-valinol (10 g, 49.3 mmol) and benzylbromide (5.86 ml, 49.3 mmol) in anhydrous dimethyl formamide (50 ml) was added at -5° C. and under nitrogen, potassium-tert-butoxide (11.06 g, 98.6 mmol) as a solid, portionwise, an in such a way that the internal temperature does not exceed +5° C. The reaction mixture was stirred for 2 hours at 0° C., diluted with ethyl acetate (2×300 ml), extracted with a 1N solution of potassium hydrogenosulfate (50 ml) and water (250 ml) and washed twice with water (2×200 ml). After drying of the organic phase on sodium sulfate, filtration and concentration in vacuo, the resulting oil was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether: 1/9, Rf: 0.42) to give the title compound as a colorless oil (9.95 g, 69% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[Cl:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])=[O:13].N1C=CC=CC=1>O1CCCC1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][S:12]([CH2:11][CH2:10][Cl:9])(=[O:14])=[O:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCOC(=O)CCS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Into a mixture of 600 ml. of tetrahydrofuran, 45.8 g. of hydroxyethyl acrylate, and 72 g. of 3-(2-chloroethylsulfonyl)propionyl chloride placed in a reaction vessel chilled with ice-water to maintain the temperature below 5° C., a solution of 31.2 g. of pyridine in 100 ml. of tetrahydrofuran was poured dropwise for 1.75 hours. The resulting mixture was stirred at room temperature for 2 hours, and poured into 2.5 l. of ice-water. The aqueous mixture was then extracted with 4 portions of 300 ml. of chloroform. The organic extract was dried over sodium sulfate, and concentrated to give 87 g. of 2-[3-(2-chloroethylsulfonyl)propionyloxy]ethyl acrylate (yield 88%).
Reaction SMILES: [Li+].[OH-].C([O:6][CH:7]([C:20]1[C:24]([OH:26])([CH3:25])[O:23][C:22](=[O:27])[CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.C(O)(=O)C>C1COCC1>[OH:6][CH:7]([C:20]1[C:24]([OH:26])([CH3:25])[O:23][C:22](=[O:27])[CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1(C)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC(O)C1=CC(=O)OC1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (0.5M, 22.6 mL, 11.32 mmol) was added to a solution of 4-(1-acetoxytridecyl)-5-hydroxy-5-methyl-2-furanone (1.00 g, 2.83 mmol) in THF (15 mL). After stirring for 3 hours at room temperature the reaction was quenched with glacial acetic acid (680 mg, 11.3 mmol) and extracted with ethylacetate. The combined organic fractions were washed with a saturated solution of aqueous sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 40% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9](Cl)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].[CH2:22]([NH2:24])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9]([NH:24][CH2:22][CH3:23])=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: CCN
Product: CCCCNc1c(C(=O)OCC)c(C)nc(NCC)c1[N+](=O)[O-]
Yield: 86 %

Procedure:
4-Butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester is treated with ethylamine according to the procedure in Example 1 c and 4-butylamino-6-ethylamino-2methyl-5-nitropyridine-3-carboxylic acid ethyl ester is obtained, yield 86%, m.p. 53°-55° (methanol).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C@H:7]([OH:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C@H:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(=O)N1c2ccc(F)cc2[C@H](O)C[C@@H]1C
Product: CC(=O)N1c2ccc(F)cc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 63 %

Procedure:
A compound was produced in the same manner as in Example 12, using 39 mg of cis-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydro quinoline and phenol, and thus 33 mg (63%) of the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC#N)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCC#N)cc1

Procedure:
4-Methoxycinnamonitrile was hydrogenated in ethanol with palladium hydroxide on carbon to give 3-(4-methoxyphenyl)propionitrile. A mixture of anhydrous cerium (III) chloride (1.99 g, 8.1 mmol) in dry THF (12 mL) was stirred for 3 hours at room temperature, cooled to −78° C., and treated with MeLi (5.8 mL, 8.1 mmol). After stirring for 1 hour at −78° C. the reaction mixture was treated with 3-(4-methoxyphenyl)propionitrile (0.45 g, 2.8 mmol). The reaction mixture was stirred for 5 hours at −78° C. and then quenched with ammonium hydroxide. After warming to room temperature, the mixture was filtered, and the filtrate diluted with water and extracted with diethyl ether. The diethyl ether layer was dried over sodium sulfate and evaporated. The crude oil was purified by normal-phase chromatography to give 150 mg of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a light yellow oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([SH:19])[CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([S:19][C:4]2[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][N:12]=2)[CH2:15]1
Reactant: CN1CCC(S)C1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2ncccc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 80 g (2 mole) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylformamide, all heated to 60° C. and using nitrogen gas flow was added dropwise, a solution of 157.0 g (1 mole) of 2-chloronicotinic acid and 117 g (1 mole) of 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a rate which maintained a temperature of 60°-67° C. The mixture was heated to 65° C. for 6 hr and allowed to stand overnight at room temperature and then filtered. The collected solid was suspended in one liter of isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a pH of 6.2 was reached. The mixture was brought to a boil and filtered. The solid was dissolved in 2 liters of water and extracted with isopropyl ether. The pH was adjusted to 6.0 and the solution was concentrated to a volume of 800 ml and placed in a refrigerator. The resulting solid (85 g) collected by filtration, was a mixture consisting of about 85% of the title compound and 15% sodium chloride. A sample portion of this was crystallized once from ethanol and twice from isopropyl alcohol-water. The recrystallized product decomposed at about 225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I.CS[C:17]1[NH:18][CH2:19][CH2:20][N:21]=1.CO>C(OCC)C>[NH:21]1[CH2:20][CH2:19][N:18]=[C:17]1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CSC1=NCCN1
Agent: I
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CN(C1=NCCN1)CC2

Procedure:
A mixture of 10 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline, 13.7 g of 2-methylsulphanyl-4,5-dihydro-1H-imidazole hydriodide and 100 ml of methanol is heated at reflux for 12 hours. The addition of diethyl ether causes the separation of a precipitate, which is taken up in water, neutralised using sodium hydroxide and extracted with dichloromethane.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[CH2:19]([NH:21][C:22](=S)[NH:23][NH2:24])[CH3:20]>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:22]([NH:21][CH2:19][CH3:20])=[N:23][N:24]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCNC(=S)NN
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(C)C(C)=O)c3)nn12
Yield: 16.9 %

Procedure:
A solution of 6.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.5 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours and treated in similar fashion to Example 67. Chromatography on silica gel and recrystalization from dichloromethane-hexane afforded 1.2 g yellow crystals, mp 225°-227° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+].O>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C)(C)CN2C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indole (2.44 g, 11.13 mmol, see PCT Int. Appl. (2001), WO 2001023374 A1 20010405) in trifluoroacetic acid (50 mL) was stirred at 0° C. and potassium nitrate (1.181 g, 11.68 mmol) was added in one portion. The reaction was maintained at 0° C. for 3 hours and poured into water. The solids were collected via filtration to afford 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.545 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1 H), 7.34 (s, 1 H), 3.91 (s, 3 H), 2.15 (s, 2 H), 1.36 (s, 6 H). Note: proton resonance corresponding to acetyl was extremely broad and/or not evident for a variety of lots.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][C:11]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:37])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1F
Reactant: Cc1noc(C)c1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2c(C)noc2C)nc1F

Procedure:
By carrying out the operation analogously to example 213, starting from 2-fluoro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained and is used directly in the deacetylation stage.