Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH:17][C:39]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[O:40])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 2) (9.1 g) in DCM (300 ml) was treated with pyridine (30 ml) and tetrahydro-2H-pyran-4-carbonyl chloride (5.0 ml) and the solution stirred under nitrogen at ambient temperature for 3.5 h and then left standing overnight (ambient temperature, under nitrogen). The volatiles were evaporated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water ×2 and the combined aqueous extracted with DCM. The combined organic phases were washed with brine, dried (hydrophobic frit) and reduced to dryness in vacuo. The combined aqueous including the brine wash (˜pH4) was basified with solid sodium hydrogen carbonate and the aqueous extracted with DCM x2. The organic fractions were dried (hydrophobic frit), combined with the previous material and reduced to dryness in vacuo to give a brown foam. This foam was further dried in vacuo, triturated with diethyl ether, the suspension chilled (ice/water bath) and the solid isolated by filtration. The solid was washed with a little diethyl ether and air-dried to give N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide as a beige solid (11.95 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[C:16]([Cl:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH2:2][CH3:3].[C-]#[N:20].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[C:16]([Cl:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:20])[CH2:2][CH3:3]
Reactant: [C-]#N
Reactant: CCCc1c(OCCCCCBr)ccc(Cl)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC#N)ccc(Cl)c1Cl

Procedure:
A solution of 1.6 g. of 5-(2-propyl-3,4dichlorophenoxy)pentyl bromide and 0.22 g. of sodium cyanide were heated overnight at 75°-85° C. in 50 ml. of dimethylformamide. The solution was evaporated in vacuo and ethyl acetate and water were added to the residue. The layers were separated and the organic layer was washed several times with a saturated sodium chloride solution. The organic solution was filtered through sodium sulfate and evaporated to dryness to give 1.38 g. of the desired sub-title intermediate. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.CN1CC(=O)OB([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)OC(=O)C1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:6]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1
Reactant: CN1CC(=O)OB(c2cccnc2)OC(=O)C1
Reactant: Clc1cc(Cl)nc(-c2nccs2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(-c2cccnc2)nc(-c2nccs2)c1
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-(4,6-dichloropyridin-2-yl)thiazole (50 mg, 0.216 mmol), 6-Methyl-2-(3-pyridinyl)-1,3,6,2-dioxazaborocane-4,8-dione (“3-Pyridineboronic acid MIDA ester”, 50.6 mg, 0.216 mmol), Pd(dppf)Cl2 (8 mg, 11 μmol) and K3PO4 (344 mg, 1.62 mmol). The vial was capped with a septum screwcap and then placed under N2 atmosphere. To the vial was added THF (1.00 mL) and water (0.20 mL). The mixture was placed in a 60° C. with stirring for 3 h. The reaction mixture was transfered to a 125 mL separatory funnel using EtOAc and water. The mixture was diluted with EtOAc (30 mL), then washed with sat. aq. NaHCO3 (20 mL). The aq. phase was extracted with EtOAc (20 mL). The combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford a solid yellow residue. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 50:50) to afford 2-(4-chloro-[2,3′-bipyridin]-6-yl)thiazole as a white solid (32 mg, 54%). 1H-NMR (400 MHz, CDCl3) δ 9.32 (dd, J=2.3, 0.8 Hz, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H), 8.43-8.37 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.98 (d, J=3.0 Hz, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.53 (d, J=3.3 Hz, 1H), 7.47 (ddd, J=7.9, 4.9, 1.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.CN(C)C=O>ClCCl.CO>[CH3:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC1NCCc2ccccc21
Reactant: Cc1cc(O)nc(Cl)n1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(N2CCc3ccccc3C2C)n1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A mixture solution of 6-methyl-2-chloro-4-hydroxypyrimidine(6 g, 37.5 mmol) prepared in the above Step 1, 1-methyl-1,2,3,4-tetrahydroisoquinoline(11.6 g, 78.8 mmol) and N,N-dimethylformamide(30 ml) was stirred at 120 for 2 hours and cooled to give a solid. The resulting solid was dissolved in a mixture solution of dichloromethane and methanol and the undissolved materials were filtered off. The filtrate residue was washed many times with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 7.1 g of titled compound. (Yield: 74.1%)
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[S:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([CH:8]([OH:9])[C@H:6]2[S:7][C@@H:1]([N:10]3[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]3=[O:12])[C@H:2]([OH:3])[C@@H:4]2[OH:5])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=c1ccn([C@@H]2S[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Compound 13 (2 g, 7.754 mmol) was dissolved in dry pyridine (20 mL), 4,4′-dimethoxytrityl chloride (2.9 g, 8.53 mmol) was added and the mixture stirred at room temperature overnight. The reaction was quenched with methanol and taken up in ethyl acetate (200 mL). The ethyl acetate solution was washed twice with saturated sodium bicarbonate solution, once with water, once with brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and the residue purified by flash chromatography (7% methanol in dichloromethane). The desired fractions were pooled and concentrated to give Compound 14 (3.0 g) in 80% yield. The structure of Compound 14 was confirmed by 1H NMR & ESMS.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCCn1c(C)c(Cc2ccccc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(Cc2ccccc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-benzyl-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C)C=O>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:15]=1)(=[O:20])=[O:21]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 55.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 150 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (58 mg, 1.46 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 1-bromomethyl-4-methanesulfonyl-benzene (364 mg, 1.46 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-(4-methanesulfonyl-benzyl)-3-nitro-1H-pyrazole (207 mg, 55%) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CCNC1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(N2CCCC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 35.5 %

Procedure:
A mixture of Example 330a (90 mg, 0.27 mmol) and pyrrolidine (668 μL, 8.08 mmol) in 1 mL DMSO was heated at 160° C. under microwave conditions for 30 minutes. The product was purified by preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (37 mg, 35.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.07 (s, 1H), 7.61 (dd, J=8.8, 2.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.26 (t, J=2.8 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.99-5.94 (m, 1H), 3.56 (s, 3H), 3.16 (q, J=7.3 Hz, 2H), 3.06 (s, 4H), 1.69 (t, J=6.3 Hz, 4H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 386.1 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH3:19][CH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:28](Cl)=[O:29])[CH2:21]1>>[CH3:19][CH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:28]([N:11]2[C:5]3=[N:6][C:7]4[C:2]([C:3](=[O:18])[N:4]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=3)=[CH:1][CH:10]=[CH:9][CH:8]=4)=[O:29])[CH2:21]1
Reactant: CC1CCCCCC(C(=O)Cl)C1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CC1CCCCCC(C(=O)n2c3ccccc3n3c(=O)c4ccccc4nc23)C1

Procedure:
6-(3-Methylcyclooctanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and 3-methylcyclooctanoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1(Br)C[CH2:19]1.O[Li].O>C(O)(C)C.O>[CH:16]1([CH2:15][S:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: BrC1CC1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(SCC2CC2)CC1
Temperature: 25 °C

Procedure:
To an argon purged solution of tert-butyl-4-(acetylthio)piperidine-1-carboxylate (51, 1.50 g, 5.86 mmol) in a 5:1 mixture of isopropanol-water (55 mL) was added cyclopropyl bromide (1.52 g, 11.72 mmol) followed by solid LiOH.H2O (1.0 g, 68.67 mmol). The mixture stirred at room temperature and stirred for 16 h and was concentrated under reduced pressure. The residue was dissolved in EtOAc (90 mL) and washed with H2O (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-(cyclopropylmethylthio)piperidine-1-carboxylate as a colorless syrup (52, 1.1 g, 69%); 1H NMR (300 MHz, CDCl3) δ 2.98-2.75 (m, 3H), 2.61 (m, 1H), 2.48 (d, J=6.9 Hz, 2H), 2.39-2.28 (m, 1H), 1.74-2.01 (m, 2H), 1.43-1.55 (m, 2H), 1.45 (s, 9H), 1.01-0.88 (m, 1H), 0.52-0.59 (m, 2H), 0.15-0.25 (m, 2H);
Reaction SMILES: C(OC1C=C(C#N)C=CC=1C=O)C1C=CC=CC=1.[Br-].C(C1C=CC(CC[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(O)=O.[CH2:50]([O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[CH:60][C:59]=1[CH:66]=[CH:67][CH2:68][C:69]1[CH:77]=[CH:76][C:72]([C:73]([OH:75])=[O:74])=[CH:71][CH:70]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(OC1C=C(C#N)C=CC=1CC=CC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.OC1C=C(C#N)C=CC=1CCCC1C=CC(C(O)=O)=CC=1>>[CH2:50]([O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[CH:60][C:59]=1[CH2:66][CH2:67][CH2:68][C:69]1[CH:70]=[CH:71][C:72]([C:73]([OH:75])=[O:74])=[CH:76][CH:77]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: N#Cc1ccc(C=CCc2ccc(C(=O)O)cc2)c(OCc2ccccc2)c1
Agent: N#Cc1ccc(C=O)c(OCc2ccccc2)c1
Agent: N#Cc1ccc(CC=Cc2ccc(C(=O)O)cc2)c(OCc2ccccc2)c1
Agent: N#Cc1ccc(CCCc2ccc(C(=O)O)cc2)c(O)c1
Product: N#Cc1ccc(CCCc2ccc(C(=O)O)cc2)c(OCc2ccccc2)c1

Procedure:
2-Benzyloxy-4-cyanobenzaldehyde and 4-carboxyphenethyltriphenylphosphonium bromide were converted to a mixture of 4-[3-(2-benzyloxy-4-cyanophenyl)prop-2-enyl]benzoic acid and 4-[3-(2-benzyloxy -4-cyanophenyl)prop-1-enyl]benzoic acid by a similar method to that of Example 1, (G). The alkenes were converted to the required 4-[3-(2-hydroxy-4-cyanophenyl)propyl)benzoic acid by a similar method to that of Example 33, Footnote a.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3-Trifluoromethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [Cl-].[Nd+3:2].[Cl-].[Cl-].[C:5](=[O:8])([OH:7])[O-:6].[Mg+2].[C:10](=[O:13])([OH:12])[O-:11].[Nd]>>[C:5](=[O:6])([O-:8])[O-:7].[Nd+3:2].[C:10](=[O:11])([O-:13])[O-:12].[C:5](=[O:6])([O-:8])[O-:7].[Nd+3:2]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Nd+3]
Product: O=C([O-])[O-]

Procedure:
Adding 6 m3 of neodymium chloride solution (1.5 mol/L) into a reactor containing 27.5 m3 of the above magnesium bicarbonate solution to react for 3 hour at 35° C., and controlling the pH value of mother liquor at 8.0, neodymium ions are precipitated, and then neodymium carbonate is obtained after filtration, washing and drying. At last, neodymium oxide is obtained from calcination of neodymium carbonate at 650° C. for 2 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].O>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)=[O:23]
Reactant: OCCC1CCNCC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)N2CCC(CCO)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-hydroxyethyl)piperidine (5.0 g) and triethylamine (5.39 ml) in methylene chloride (50 ml) was added dropwise a solution of 3-methoxybenzoyl chloride (5.44 ml) in methylene chloride (15 ml) at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-(3-methoxybenzoyl)piperidin-4-yl]ethanol (9.6 g) as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccncc3)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ccncc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (cf. Example 40 below) as described in Example 1 to give 3-[4-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[ClH:35].O1CCOCC1>O1CCCC1>[ClH:35].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNCc1cn(S(=O)(=O)c2ccc(C(C)O)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(1-hydroxyethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (176 mg) in tetrahydrofuran (2 mL) was added 4 mol/L hydrogen chloride-dioxane solution (3 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 95.5 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:13][NH2:14].O>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chlorophenoxyacetyl chloride (2 g) in tetrahydrofuran (40 ml) at 0° C. was added methylamine (2M, 12.2 ml). The reaction was allowed to warm to room temperature, and stirred for 1 h, before water (30 ml) added and the tetrahydrofuran removed in vacuo. The aqueous was extracted with ethyl acetate (2×50 ml), the combined organic extracts washed with brine (40 ml), dried over magnesium sulphate (1 g) and the solvent removed in vacuo to yield the title compound as a white solid (1.67 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](C)=[CH:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.O.[C:29]([O-:32])(O)=O.[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:29](=[O:32])[CH:10]2[CH3:9])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: O=C([O-])O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)C(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dihydro-7-methoxy-4-methylnapthalene (20.87 g) was dissolved in isopropanol (100 ml) and cooled in an ice bath. Monoperoxyphthalic acid magnesium salt (mmpp) (17 g) was added, then water (50 ml) was added and the mixture was stirred at room temperature for 2 hours. When oxidation was complete, the product mixture was hydrolyzed with aqueous NaHCO3, partially evaporated and extracted with ethylacetate. The latter extract was washed with brine and evaporated. The residue was dissolved in a mixture of ethanol (156 ml), water (121 ml) and conc. H2SO4 (24.3 ml), and heated to reflux under N2 atmosphere for 3 hours, cooled and neutralized with NaHCO3. After partial evaporation, the residue was extracted with ethylacetate, washed with brine, dried over MgSO4 and evaporated. The product was purified on a silica gel column using a mixture of hexanes and ethylacetate (100:1, 50:1, 50:1.5). The yield of the product was 16.2 g (71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([NH:13][C:14](=[O:17])[CH2:15]Cl)[CH2:10][CH:9]2[CH2:11][OH:12])[CH:7]=1.CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]23[CH2:10][CH:9]2[CH2:11][O:12][CH2:15][C:14](=[O:17])[NH:13]3)[CH:7]=1
Reactant: O=C(CCl)NC1(c2cc(Br)ccc2F)CC1CO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCC2CC2(c2cc(Br)ccc2F)N1
Temperature: 23 °C
Reaction time: 19 h
Yield: 91.8 %

Procedure:
To a suspension of N-[(1SR,2RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxymethyl-cyclopropyl]-2-chloro-acetamide (intermediate B9A) (495 mg, 1.47 mmol) in tert-butanol (6 ml) at 23° C. was added potassium tert-butoxide (KOBut) (550 mg, 4.9 mmol) in one portion [exothermic] and the mixture was stirred at 23° C. for 19 h. Poured into 1 M HCl, extracted with ethyl acetate, washed organic layer with brine, dried over sodium sulfate. Removal of the solvent in vacuum left an orange oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound as a white gum (405 mg, 92%). MS (ISP): m/z=300.1 [(M+H)−] and 302.2 [(M+2+H)+].
Reaction SMILES: O.[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccccc1O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 200 ml of water, 200 ml of ether and 20.0 g of 2-isopropylphenol was added dropwise 22.0 ml of 61% nitric acid, and then the mixture was reacted with stirring at room temperature for 2 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. After, the drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1:1)] to give 7.69 g of 6-isopropyl-2-nitrophenol.