Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 19 (0.31 g, 0.63 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.2 mL, 1.2 mmol) and DMAP (5 mg, 0.04 mmol). Methanesulfonyl chloride (0.08 mL, 1 mmol) was added. After 2 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 20 as an orange-colored oil (362 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C(OCC)(=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(Br)c(C(=O)O)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)ccc1Br
Reaction time: 72 h

Procedure:
To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the reaction mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and washed with aqueous saturated Na2CO3 solution (twice) and brine, then dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:18][CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 44A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.24 Hz, 1H) 7.76 (s, 1H) 7.47 (d, J=7.63 Hz, 1H) 7.40 (dd, J=8.54, 1.53 Hz, 1H) 7.08 (d, J=7.63 Hz, 1H) 3.83-3.92 (m, 1H) 3.42-3.53 (m, 1H) 2.92-3.04 (m, 1H) 2.62-2.74 (m, 3H) 2.60 (s, 3H) 2.50 (s, 3H) 2.08 (s, 4H) 1.71-1.83 (m, 4H) 1.50-1.61 (m, 2H). MS: (M+H)+=378.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>CCO.CCOC(C)=O.O=[Mn]=O>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]=[O:11])=[C:2]([Br:1])[CH:7]=1
Reactant: OCc1ccc(CBr)cc1Br
Agent: O=[Mn]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CBr)cc1Br
Yield: 80.6 %

Procedure:
The compound of Step 2 (8 g, 29 mmol, 1 eq) was dissolved in 10% EtOH/EtOAc (300 ml) and 5 eq of MnO2 (12.4 g, 142 mmol) was added every hour for 6 hours. The mixture was filtered through Celite and the solvent was removed under vacuum to give 6.5 g (80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(CCl)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)methanol (Claudi, et al., J. Med. Chem. 1990, 33(9):2408) (0.90 g, 5.76 mmol) in anhydrous dichloromethane (10 mL) was added thionyl chloride (0.84 mL, 12 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo to afford 4-(chloromethyl)-1-fluoro-2-methoxybenzene (0.73 g, 72%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.05-6.86 (m, 3H), 4.53 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:45]1([CH:48]=O)[CH2:47][CH2:46]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:35]4[CH2:48][CH:45]4[CH2:47][CH2:46]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=CC1CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4CC4CC4)ncn3)cccc2s1

Procedure:
(2S,5R)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-5-phenylpyrrolidine-2-carboxamide, Example 60, (62 mg, 0.1 mmol) was reacted with cyclopropanecarboxaldehyde (0.009 mL, 0.12 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 673 (M+1).
Reaction SMILES: [CH2:1]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[Na+].Cl[CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:20])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 6.36 g. of 4-(n-tridecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and the 1-chloro-2,3-propanediol in the manner described in Example 2 to yield 2,3-dihydroxypropyl 4-(n-tridecylamino)benzoate as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:24])[C:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=2)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Cl:25])[CH:5]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:25][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: -15 °C
Yield: 44 %

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid methyl ester (488 mg, Example 135) was dissolved in CH2Cl2 under argon. The solution was cooled to −15° C. in an ice/salt bath and a solution of DIBAL-H (1M in CH2Cl2, 3 mL) was added drop wise. Stirring was continued and the mixture was allowed to warm to 0° C. over a period of 2 hours. The mixture was then poured into ice/water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (200 mg). MS (m/e)=380.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:19](=[CH:23][N:24]([C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=4)[N:25]=3)[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:24]2[CH:23]=[C:19]3[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([O:8][C:9]5[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=5)=[C:2]([CH3:1])[CH:3]=4)[C:18]3=[N:25]2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cn(-c5ccc([N+](=O)[O-])cc5)nc34)cc2C)cn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cn(-c5ccc(N)cc5)nc34)cc2C)cn1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (200 mg) in a mixed solvent of ethanol/water (9:1, 6 mL) was added calcium chloride (90%, 28 mg) and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 164 mg) was added at room temperature, and the mixture was stirred at 100° C. for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride=10/1) to give the title compound (140 mg) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:16](OCC)(=[O:18])C>CO>[CH3:16][O:18][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1cccc(F)n1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(C)(C)C#N)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 2-(6-fluoropyridin-2-yl)-2-methylpropanenitrile (10 g) in methanol (30 mL) was added sodium methoxide (50 mL of a 30% solution in methanol). The reaction was then refluxed for 1 h, cooled to rt, poured into ethyl acetate (400 mL), and washed with brine (3×200 mL). The organic layer was dried over Na2SO4 and concentrated to give 2-(6-methoxypyridin-2-yl)-2-methylpropanenitrile (9.8 g, 92%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH:9](C)C#N)[CH3:8]>[Pd]>[CH3:9][N:7]([CH3:6])[CH2:8][CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: CCNCC
Reactant: CC(C#N)N(C)C
Agent: [Pd]
Product: CN(C)CCCNCCCN(C)C
Yield: 58 %

Procedure:
GB-A 1,157,637, GB-A 1,157,638 and GB-A 1,157,639 disclose the reaction of 2-methylglutarodinitrile with diethylamine in the presence of hydrogen and palladium on barium sulfate or preferably palladium on carbon to form 5-diethylamino-2-methylvaleronitrile. Despite the long reaction time and a diethylamine excess of 200 mol % no tetraethyl derivative was found, although the diethylamino group reacts not only with the nitrile groups in position 5 but also with that in position 1 (ratio 4 to 1). DE-A 3,935,641 describes the synthesis of a secondary amine over a palladium catalyst. The reaction of dimethylaminopropionitrile takes place in this case with itself under hydrogenating conditions to form bis(3-dimethylaminopropyl)amine. The formation of a tertiary amine is achieved only when a spinel is used as support material which is considerably expensive to produce, and the yield is not more than 58%.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]=[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.[OH-].[K+].CO.Cl>O>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:6]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=2)=[CH:5][C:4]([OH:27])=[O:3])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCOC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(C(=CC(=O)O)c2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester (0.76 g, 2.05 mmol), potassium hydroxide (5 N, 8.10 ml, 20.52 mmol), methanol (6 ml), and H2O (1.5 ml) were mixed and stirred at rt for a couple of hours. The methanol was evaporated in vacuo leaving a clear solution, which was extracted with ether (2×60 ml) to get rid of the impurities. The aqueous phase was acidified with conc. HCl to pH around 2˜3 to form a white precipitation, which was extracted with CH2Cl2 (2×100 ml), dried over MgSO4, filtered and concentrated to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid as a foamy solid (0.69 g, 98%); mp, 90-92° C.: 1HNMR (CDCl3) δ 6.90-6.75 (m, 4H, double bond protons and 2COOH), 6.50-6.24 (m, 12H, Ar), 3.92-3.75 (multiple singlets, 24H, 8OCH3), isomer ratio based on 1HNMR close to 43%:57%; Anal. Calcd. For C19H20O6: C, 66.27; H, 5.85. Found: C, 66.02; H, 5.81.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30](=[NH:33])SC)=[O:28])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[NH:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CSC(=N)NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NC(=O)Cc1ccc(F)cc1)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a test tube containing 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.082 mmol) and 1-(2-(4-fluorophenyl)acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) was added 0.3 mL of toluene followed by diisopropylethylamine (15 μL, 0.086 mmol). The reaction was stirred at 110° C. for 6 h. Additional portions of 1-(2-(4-fluorophenyl)-acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) and diisopropylethylamine (15 μL, 0.086 mmol) were added. After stirring at 110° C. overnight, the reaction was cooled to room temperature and purified directly by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) to give the title compound as a white solid. The solid was treated with 4 N HCl in dioxane at 0° C. for 30 min. The solution was concentrated in vacuo to give the HCl salt of the title compound (15 mg, 40%) as a white powder. 1H NMR (CDCl3) δ 13.8 (br s, 1H), 11.5 (br s, 1H), 9.48 (br s, 1H), 7.85 (s, 1H), 7.78 (dd, 1H, J=2.5, 1.4 Hz), 7.30 (m, 5H), 7.01 (m, 3H), 6.85 (m, 1H); MS(ESI+) m/z 423.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:17](O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Subsequently, to a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (2.5 g, 14.4 mmol) in dimethylformamide (125 ml) was added sodium hydride (55% oil dispersion) in an ice bath. After stirring the mixture for 10 minutes in the ice bath, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methyl iodide (1.79 ml, 28 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the reaction mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution was added thereto in an ice bath and the reaction mixture was stirred in the ice bath for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 1-t-butoxycarbonyl-3-methoxyazetidine (2.18 g, yield 81%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[C:28]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:26][CH:25]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)cc4)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(F)cc3)C2)n1
Temperature: 150 °C
Yield: 21.6 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-fluorophenyl)-3-piperidinecarboxamide (90 mg, 0.207 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.621 mmol), and hydrazine anhydrous (0.026 mL, 0.829 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes in microwave. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered, and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 1H), 1.85 (m, 2H), 2.07 (m, 1H), 3.17 (m, 2H), 4.52 (m, 1H), 4.74 (m, 1H), 4.98 (m, 1H), 6.94-7.08 (m, 1H), 7.16 (m, 2H), 7.39 (s, 1H), 7.56-7.69 (m, 2H), 7.73 (s, 1H), 7.82-8.04 (m, 1H), 10.13 (m, 1H), 11.86-12.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: Fc1ccc(Br)cc1
Product: Brc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1

Procedure:
In analogy to example 4.6, 5-benzyloxy-indole and and 1-bromo-4-fluoro-benzene were converted to yield 5-Benzyloxy-1-(4-bromo-phenyl)-1H-indole as light brown solid, mp 118° C., MS: 377 (M, 1Br).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([O:13][CH3:14])[C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=[O:8]>CCO.O.[Fe]>[NH2:10][C:5]1[C:4]([O:13][CH3:14])=[C:3]([OH:15])[C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1c(O)c(Br)cc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: COc1c(N)c(C=O)cc(Br)c1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To the mixture of phenol 154 (25.4 g, 92 mmol) in EtOH/H2O (350 mL/100 mL) were added FeSO47H2O (4.7 g) and Fe powder (47 g). The mixture was stirred at 100° C. for 1 hr. The mixture was cooled down to 50° C. and filtered to remove inorganic materials through celite. The filtrate was concentrated in vacuo to provide the title compound 155 (19.0 g, 84%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[C:4]1=[O:16])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:17](=[O:25])[N:15]=3)[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: CCN1CCN(c2ccnc(C#N)c2)C1=O
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Yield: 52.3 %

Procedure:
4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridinecarbonitrile (0.16 g, 0.76 mmol) and methyl thiosalicylate (0.42 g, 2.5 mmol) was dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 9 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.14 g, 51%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH:25]=1)[NH2:24].[OH-].[Na+]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 63.4 %

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol) and 5-hydroxy-2-nitroaniline (52 mg, 0.34 mmol) similar to Example 180. The reaction mixture was neutralized with 2N NaOH to pH 7.0 and the solvent was removed under vacuo. The product was purified by column chromatography (20% ethyl acetate in hexane) to give 55 mg (63%) of the title compound as a light yellow solid. 1H NMR (CDCl3): 9.40 (d, J=1.2 Hz, 1H), 8.71 (dd, J=1.2, 4.8 Hz, 1H), 8.57 (ddd, J=2.1, 3.9, 7.8 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.42 (dd, J=3.9, 8.7 Hz, 1H), 7.32 (dd, J=6.0, 9.0 Hz, 1H), 7.23 (s, 1H), 6.92 (d, J=9.0 Hz, 1H), 6.19 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:26])=[C:9]([CH2:12][CH2:13][CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH2:5][C:4]1=[O:27])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]3[O:26][CH2:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH2:5][C:4]1=[O:27])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(O)c(CCCOS(=O)(=O)c3ccc(C)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)Cc2cc3c(cc21)C=CCO3
Yield: 60 %

Procedure:
A mixture of 1.65 g. (4.41 mmoles) of 1-ethyl-5-hydroxy-6-(3-tosyloxypropyl)oxindole and 610 mg. (4.41 mmoles) of potassium carbonate in 90 ml. of acetone was heated at reflux for 2.5 hours. The reaction was cooled, filtered and the filtrate evaporated. The crude residue was purified by chromatographing on 100 g. of silica gel, using 66% diethyl ether-hexane as the eluent, to give 571 mg. (60% yield) of the desired intermediate.