Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[O:19][C:18]([C@@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[N:17][N:16]=2)=[N:4][C:5]([O:13][CH3:14])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:7]=1Cl.[CH3:27][C:28]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:15]2[O:19][C:18]([C@@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[N:17][N:16]=2)=[N:4][C:5]([O:13][CH3:14])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:7]=1[CH:27]=[CH2:28]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1nc(-c2nnc([C@](C)(O)C(F)(F)F)o2)c(N)c(Cl)c1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(5-(3-amino-4-chloro-6-methoxy-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Ex 13.1) (160 mg, 0.393 mmol) in MeCN (1 ml) was added bis(triphenyl phosphine)palladium(II) chloride (Aldrich) (83 mg, 0.118 mmol) followed by 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Sigma Aldrich)(0.087 ml, 0.511 mmol). 2M Sodium carbonate (0.885 ml, 1.770 mmol) was added and the resulting mixture was heated at 130° C. for 30 minutes using microwave radiation. The mixture was filtered through Celite® and washed through with EtOAc. The filtrate was diluted further with EtOAc (50 ml) and washed with sat.NaHCO3, water, brine and dried over MgSO4. Isolute Si-TMT (2,4,6-trimercaptotriazine silica, palladium scavenger) was added the mixture was stirred for 30 mins and filtered. The solvent was removed in vacuo to afford the title compound which was used without further purification;
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])[CH2:8][CH2:7]2)=[CH:12]1
Reactant: CNC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: S=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
3-[2-(4-Methylaminopiperidyl)ethyl]indole (1.28 g, 0.005 mole) was stirred in dry benzene (75 ml) and treated with phenyl isothiocyanate (0.74 g, 0.0055 mole). Stirring was continued for 24 hr. and the mixture evaporated to give the title compound, which was converted to the hydrochloride by addition of hydrogen chloride in ethanol and precipitation with ether. Yield, 0.95 g, m.p. 193.7°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-])=O)=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=[C:3]1[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>CO.[Pd]>[NH2:9][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[N:4][C:5]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: CN1CCC(c2nc(-c3ccncc3)c([N+](=O)[O-])c(=O)n2C)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2nc(-c3ccncc3)c(N)c(=O)n2C)CC1
Reaction time: 8 h

Procedure:
To a stirring solution of 3-methyl-2-(1-methyl-piperidin-4-yl)-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (0.34 mmol) in methanol was added Pd/C (20 mg) and the reaction was stirred overnight under a hydrogen filled balloon. The reaction was filtered through celite then the product was purified on silica. M+1=299.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([S:25][CH3:26])[CH2:16][N:15]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:14]1=[O:24].C(N(CC)CC)C.N1C=CC=CC=1.[O:40]([CH2:47][C:48](Cl)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[Si:17]([N:15]1[CH2:16][C:13]([S:25][CH3:26])([NH:12][C:48](=[O:49])[CH2:47][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:14]1=[O:24])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CSC1(N)CN([Si](C)(C)C(C)(C)C)C1=O
Reactant: O=C(Cl)COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1(NC(=O)COc2ccccc2)CN([Si](C)(C)C(C)(C)C)C1=O

Procedure:
A suspension of (23) (830)mg) in dry dichloromethane (20 ml) at -10° C. was treated with triethylamine (220 mg) and pyridine (172 mg), followed by a solution of phenoxyacetyl chloride (372 mg) in dry dichloromethane (~4 ml). The mixture was washed with very dilute HCl, followed by brine. The organic phase was dried and the solvent evaporated. Chromatography on silica yet gave the product (24) (730 mg). νmax (CHCL3) 3400, 1745, and 1690 cm-1 ; δppm (CDCl3) (90 MHz) 0.25 and 0.27 (boths, together 6H), 0.98 (S, 9H), 2.22 (S, 3H), 3.36 and 3.81 (ABq, 2H, J 7.0 Hz), 4.50 (S, 2H), 6.80 to 7.50 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[CH2:19]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:17][CH2:15][CH2:2][CH2:3][CH3:4])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CCCCOc1cccc2c1C(=O)c1c(OCCCC)cccc1C2=O
Temperature: 25 °C
Yield: 154.4 %

Procedure:
A suspension of 1,8-dihydroxyanthraquinone (35.0 g, 0.14 mol), butyltosylate (93 g, 0.6 mol), and sodium carbonate (38 g, 0.36 mol) in 700 mL of o-dichlorobenzene was heated at reflux for 6 days. The mixture was cooled to room temperature, filtered, and the solvent was removed by steam distillation. The residue was recrystallized from isopropanol to provide 38.1 g (74% yield) of 1,8-dibutoxyanthraquinone, which has the structural formula: ##STR48##
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH3:36])[CH2:24][C:25]([O:27]C)=[O:26])#[N:22]>>[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:31][C:30]=1[CH3:36])[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1C
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)c(C)c2)cc1)c1ccccc1
Yield: 95.69 %

Procedure:
Compound 62 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.5 g, 1.85 mmol) and methyl 3-cyano-3-(4-hydroxy-2-methylphenyl)propanoate (0.404 g, 1.85 mmol) by following the procedure described in scheme 18 (0.65 g, yield: 95.69%); Purity: 93.64%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CN(C)[C:16](=[O:18])C.O1CCCC1.[H-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:18][CH3:16])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(SC)nc(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in Example 320(1)) 5.00 g, N,N-dimethylacetamide 50 ml, tetrahydrofuran 20 ml and sodium hydride (60%) 1.673 g is stirred for 20 minutes on an ice bath. Methanol 5 ml is dropped thereto over a period of 30 minutes and the mixture is stirred for 15 minutes. The reaction mixture is diluted with a 10% aqueous citric solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The resulting solid is triturated with hexane in ice to give 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine as a slightly brown crystalline powder, 4.61 g. mp 179-181° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH:13]([OH:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)CCCc2ccccc2)ccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)CCCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 9.0 g of 4-(benzyloxy)-3-methoxy-α-(3-phenylpropyl)benzyl alcohol in 250 ml of methylene chloride is treated with 90 g of manganese dioxide and held at the reflux temperature for 2 hours. After cooling, the precipitate is filtered under suction and washed with methylene chloride. The filtrate is evaporated and the residue is recrystallized from ethyl acetate/ether. There is obtained 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in the form of colorless crystals of m.p. 81°-82°.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>O1CCCC1>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:7]([O:6][C:5]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:24]=[CH:25][C:4]=1[C:1](=[S:42])[NH2:2])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(N)=O)c1ccccc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(N)=S)c1ccccc1C
Temperature: 25 °C
Yield: 142.7 %

Procedure:
A stirred solution of ethyl (RS)-4-[2-carbamoyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (2.44 g) in tetrahydrofuran (49 mL) is treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (1.08 g) and maintained at 25° C. for 24 hours. The solution is then evaporated and the residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (2:1 v/v), followed by trituration with diethyl ether, to give ethyl (RS)-4-(2-methylphenyl)-4-[5-(3-thienylmethoxy)-2-thiocarbamoylphenoxy]butanoate (1.79 g) in the form of a yellow solid, m.p. 134-135° C. [NMR(CDCl3):- 1.2(3H,t),2.2-2.6(4H,m), 2.4(3H,s),4.1(2H,q), 4.9(2H,q),5.6(1H,m),6.2-7.8(9H,m),8.7(1H,d)].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:7]12.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH:25]=[O:26])=[C:13]([CH3:15])[N:12]=[C:7]12
Reactant: CN(C)C=O
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C=O
Temperature: 87.5 °C
Reaction time: 6 h

Procedure:
A solution of 7-chloro-2-methylimidazo[2,1-a]isoquinoline (4 g) in N,N-dimethylformamide (40 ml) was added dropwise to a mixture of N,N-dimethylformamide (5.7 ml) and phosphoryl chloride (1.86 ml) under ice cooling. After being stirred at 85-90° C. for 6 hours, the mixture was poured into ice-water, basified with aqueous sodium hydroxide, heated at 80° C. for 20 minutes and cooled. The resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give 7-chloro-3-formyl-2methylimidazo[2,1-a]isoquinoline (0.356 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].OC1C=CC=CN=1.[CH2:16]([O:23][C:24](=[O:56])[NH:25][C@H:26]([C@@H:47]1[CH2:51][C@@H:50]([CH:52]([CH3:54])[CH3:53])[C:49](=[O:55])[O:48]1)[CH2:27][N:28]1[CH2:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH2:42][O:43][CH3:44])[CH2:30][C:29]1([CH3:46])[CH3:45])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[CH2:16]([O:23][C:24](=[O:56])[NH:25][C@@H:26]([CH2:27][N:28]1[CH2:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH2:42][O:43][CH3:44])[CH2:30][C:29]1([CH3:45])[CH3:46])[C@@H:47]([OH:48])[CH2:51][C@H:50]([C:49](=[O:55])[NH:1][CH2:2][C:3]([C:4](=[O:5])[NH2:6])([CH3:8])[CH3:7])[CH:52]([CH3:53])[CH3:54])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: CC(C)(CN)C(N)=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)CC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
161 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.39 mmol) and 44 mg of 2-hydroxypyridine (0.46 mmol) were added to a solution of 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester obtained in the above reaction (0.46 mmol) in triethylamine (4.6 ml), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 9 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/3) to obtain 166 mg of {(1S,2S,4S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-2-hydroxy-1-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-5-methylhexyl}carbamic acid benzyl ester (yield: 52%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][N+:20]([O-:22])=[O:21].C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1>CCOC(C)=O>[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH:19]([N+:20]([O-:22])=[O:21])[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: O=CCCCOCc1ccccc1
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C(O)CCCOCc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-benzyloxybutanal (1.463 g, 8.2 mmol), methyl-4-nitrobutyrate (1.29 g, 8.8 mmol) and (−)-sparteine (206 mg, 0.88 mmol) are combined and stirred at RT for 6 hours. EtOAc (5 mL) is added, and the solution is filtered through silica. The solvent is removed in vacuo to yield a pale yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=1)=[O:9].Cl>>[OH:17][C:13]1[CH:12]=[C:11]2[C:16]([CH2:6][CH2:7][C:8](=[O:9])[NH:10]2)=[CH:15][CH:14]=1
Reactant: COc1cccc(NC(=O)CCCl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2ccc(O)cc2N1
Temperature: 200 °C
Yield: 54.7 %

Procedure:
Under nitrogen with outlet to back of hood, added 12.37 g of aluminum chloride powder (0.093 mol) to 7.93 g of 3-Chloro-N-(3-methoxy-phenyl)-propionamide (0.037 mol). Placed in preheated 160° C. sand bath, and heated for 4 hours, raising bath temperature to 200° C., until no more HCl is observed. Cooled to room temperature, chilled in ice bath and cautiously added ice-H2O. Extracted three times with EtOAc, dried (MgSO4), and evaporated under reduced pressure. Purified by flash chromatography on 230–400 Å mesh silica gel, eluting with 1:1 EtOAc/Hexanes to give 3.3 g of beige solid (55%). 1H NMR (400 MHz, CDCl3) δ 2.60 (2H, q, J=6.23 Hz), 2.88 (2H, t, J=6.85 Hz), 6.23 (1H, d, J=2.49 Hz), 6.44 (1H, q, J=2.49 Hz), 7.00 (1H, d, J=8.09 Hz). M/z (APCI+) 163.7 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[C:17](O)=[O:18])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3][CH:2]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(=O)(O)[O-].[Na+].CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[C:23]([F:26])([F:24])[F:25])[C:17]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:36])([F:37])[F:27])[CH:30]=3)=[O:18])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3][CH:2]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Nc2ncccc2-c2ccncn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)c(Nc2ncccc2-c2ccncn2)c1
Reaction time: 16 h

Procedure:
3-(3-(Pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoic acid (0.13 g, 0.36 mmol), 3-(trifluoromethyl)benzenamine (0.070 g, 0.43 mmol), TBTU (0.14 g, 0.43 mmol), DIPEA (0.13 ml, 0.72 mmol) were all mixed together in a 25 ml flask containing 3 ml of DMF. The mixture was stirred together at room temperatur for 16 hours. The reaction was then diluted with an aqueous saturated solution of sodium bicarbonate and extracted with DCM. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and the purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to give 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)benzamide as an off-white solid. MS m/z=504 [M+1]+. Calc'd for C24H15F6N5O: 503.12.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[N:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(N)CC2)nc1N
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(NS(C)(=O)=O)CC2)nc1N

Procedure:
A similar procedure as described in Example 60 was used, starting from [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl-phenyl)-methanone (Example 337) and methanesulfonyl chloride (Aldrich) to give N-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-methanesulfonamide. MS (M+H)+, 398.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[C:9]#[CH:10]
Reactant: O=C1NC(=S)CS1
Reactant: C#CCN
Solvent: CCO
Product: C#CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-thioxo-1,3-thiazolidin-2-one (12.8 g) in ethanol (200 mL) was added propargylamine (9.67 mL), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, and washed with ethanol to give the title compound (11.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[CH3:22][S+](C)(C)=O.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]3=[O:13])[CH2:22]2)=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C2(CC2c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
To a cooled solution of 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.48 g) in DMF (20 mL) at 0-5° C. was added by dropwise addition a prepared solution of the dimethylsufoxonium-methylide from sodium hydride (60% in oil) (0.209 g), trimethylsulfoxonium iodide (1.152 g) in DMF (20 mL) at room temperature. Upon completion of addition the mixture was stirred at this temperature for a further 20 min. The mixture was then carefully poured onto a stirred mixture of ice/water and ethyl acetate. The crude product was extracted into ethyl acetate, washed well with saturated brine and dried over sodium sulfate. Filtration and evaporation gave the crude product. This sample was then recrystallised from a mixture of ethyl acetate:isohexane (3:1) to give the subtitle compound (0.670 g) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 89 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (5.0 g, 15.4 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (1.93 g, 15.4 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as an orange solid (5.64 g, 13.7 mmol, 89%). δH (D-6 DMSO, 300K) 9.75 (1H, s), 8.00 (2H, s), 3.57 (3H, s), 1.93 (3H, s), 1.72 (3H, s). m/z (ES+, 70V) 413.9 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][C:29]2=[O:32])=[CH:25][CH:24]=1.Cl[CH2:34][C:35](=[O:37])[CH3:36].[Cl-].[Na+]>O1CCCC1>[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH:28]([CH2:34][C:35](=[O:37])[CH3:36])[C:29]2=[O:32])=[CH:25][CH:24]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A solution of LDA, prepared at 0° from 3.12 ml of diisopropyl-amine and 13.8 ml of n-butyllithium (1.6N in hexane), in 40 ml of anhydrous tetrahydrofuran was added dropwise while stirring during 10 minutes to a solution, cooled to -70°, of 2.96 g of 6-methoxy-1-indanone in 300 ml of anhydrous tetrahydrofuran. After 15 minutes, a solution of 1.62 ml of chloroacetone in 40 ml of anhydrous tetrahydrofuran was added dropwise to the solution during 5 minutes and the mixture was subsequently stirred at room temperature for 2 hours. The reaction mixture was poured on to 150 ml of ice Thereafter 150 ml of saturated sodium chloride solution were added and the mixture was extracted twice with 300 ml of diethyl ether each time. The combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane/diethyl ether 3:2, then 2:3). 1.8 g (45%) of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone were obtained as a red oil.