Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1

Procedure:
To a solution of 100 mg (0.23 mol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole in 16 ml of dioxane and 4 ml of water, 90 mg (0.46 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 52 mg (0.046 mmol) of palladium tetrakis and 150 mg (0.46 mmol) mg of cesium carbonate were added successively. The mixture was submitted to microwave irradiation at 120° C. for 30 minutes in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3) 78 mg (88%) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[OH:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)OCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
2-Methoxybenzoyl chloride (about 51 g) from Example 1a was added dropwise to a mixture of 2-hydroxyacetophenone (27.2 g, 24.1 ml, 0.20 mol) and pyridine (40 ml). The reaction mixture was warmed to about 60° C. exothermically. After stirring for 15 minutes, the reaction mixture was poured onto a mixture of ice (800 g) and 36% hydrochloric acid (120 ml). The solid was filtered off, washed with water, and dried. The crude product was crystallized from methanol to yield 48.4 g (89.6%) of the compound (m.p.: 78-79° C.).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([O:39][C@H:40]3[CH2:44][CH2:43][O:42][CH2:41]3)=[CH:35][CH:34]=2)O1>>[CH3:15][C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[N:4]=[C:3]([O:16][CH:17]3[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]3)[C:2]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C@H:40]4[CH2:44][CH2:43][O:42][CH2:41]4)=[CH:35][CH:34]=3)=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Reactant: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Product: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(O[C@H]3CCOC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, 5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine was reacted with (S)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane to provide the title compound (105 mg, 46% yield). 1H NMR (CDCl3, 400 MHz) 8.12 (s, 1H), 7.38 (m, 2H), 6.91 (m, 2H), 5.34 (m, 1H), 5.20 (sb, 1H), 4.95 (m, 1H), 4.31 (m, 2H), 4.09-3.92 (m, 6H), 2.90 (s, 3H), 2.22 (m, 2H), 1.80-1.57 (m, 6H), 1.23 (m, 2H), 0.94 (d, 3H). MS (ESI) m/z: Calc. 502.2 (M+). Found: 503.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)CCC.CN(C=O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing tert-butyl 5-bromopicolinate 41-1 (1.55 g, 6.0 mmol), 2-(tributylstannyl)pyrazine 41-2 (2.21 g, 6.0 mmol) and Pd(PPh3)4 (426 mg, 0.6 mmol) under argon was added DMF (15 mL). The mixture was stirred at 120° C. for 10 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 5-(pyrazin-2-yl)picolinate 41-3 as a pale yellow solid. MS m/z 258.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccccc2c1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a solution of XXII (6.0 g, 24.56 mmol) in 150 mL of MeOH was added acetic acid (18 mL). The mixture was bubbled with argon for 15 min, then palladium hydroxide (20% palladium on carbon, 1.2 g) was added to the flask. The resulting suspension was subjected to hydrogenation under 45 psi for 16 h before filtered. The filtrate was concentrated and the residue was dissolved in CH2Cl2. The resulting CH2Cl2 solution was washed with saturated NaHCO3, dried over Na2SO4 and concentrated. The residue was purified through silica gel to give (1,2,3,4-tetrahydro-quinoline-3-yl)-carbamic acid tert-butyl ester XXIII (4.2 g, 68%).
Reaction SMILES: [OH-].[Na+].O.[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH2:21])(=[O:20])=[O:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:22]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CC(C)=O>[CH:4]1([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[S:18]([NH:21][C:30]([NH:29][CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:31])(=[O:20])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C=NC1CCCCCC1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCCC1)NS(=O)(=O)c1cnccc1NC1CCCCCC1

Procedure:
0.01 mol of NaOH in solution in a minimum of water is added to a solution of 2.4 g of (4-(cycloheptylamino)pyrid-3-yl)sulphonamide in 80 cm3 of a mixture of water and acetone (1/1). Stirring is effected with a bar magnet and 2.1 g of cycloheptyl isocyanate are added. Stirring is continued while monitoring the progress of the reaction by thin layer chromatography. Evaporation is carried out in vacuo and the residue is taken up in 100 cm3 of 0.2N NaOH. After filtering, the pH of the solution is adjusted to 6.5 and the resulting precipitate is suction-filtered and then dried. The N-{[4-(cycloheptylamino)pyrid-3-yl]sulphonyl}-N'-(cycloheptyl)urea so obtained may optionally be recrystallised from an aqueous alcoholic solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: O=Cc1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COc1ccc2oc(-c3ccc(F)cc3)nc2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-4-methoxyphenol (3.07 g, 22.09 mmol) and 4-fluorobenzaldehyde (3.55 mL, 33.14 mmol) in 40 mL of methanol was stirred at 45° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (50 mL), to which was added DDQ (6.02 g, 26.51 mmol) slowly. The resulting mixture was stirred at room temperature for 45 minutes. The solvent was evaporated under reduced pressure, and to the residue was added 300 mL of ethyl acetate. The organic layer was washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated under reduced pressure. Column chromatography (ethyl acetate:Hexanes=1:9) gave 2-(4-fluorophenyl)-5-methoxybenzoxazole as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH3:21]>CN1C(=O)CCC1>[CH2:20]([O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: CCBr
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (400 mg, 2.51 mmol), Cs2CO3 (2.46 g, 7.54 mmol) and NMP (12 mL) was added bromoethane (0.563 mL, 7.54 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 5:1 hexanes:EtOAc) to give 7-ethoxy-2-methylquinoline (416 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3)c2cc1C#N
Yield: 87.6 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(5-methylisoxazol-3-yl)carbamate (72 mg) were added to toluene (5 ml), and then diisopropylethylamine (0.50 ml) was added and the mixture was heated to reflux for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate/toluene (1/1) mixed solvent to obtain the title compound (120 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc3ccccc3c2)n1
Product: c1ccc2cc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)ccc2c1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-naphthyl)-oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-naphthyl)oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 131-132° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A dried 50 mL of flask was charged sodium hydride, 60% dispersion in mineral oil (624 mg, 15.6 mmol) under N2 and then washed with dried hexane (20 mL) twice. Dried ethyl ether (10 mL) was added and a solution of 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethanol (90% ee) (2.5 g, 12.89 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred for 1 h. A solution of trifluoromethanesulfonyl chloride (3.28 g, 19.5 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction was allowed to warm up to room temperature and stirred for 1 h. The solvent was removed under rot-vap and diluted with hexane (150 mL) and washed with a saturated NaHCO3 n and brine. After drying with MgSO4, the organic solvent was removed to give trifluor-methanesulfonic acid 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethyl ester (3.15 g) (90% ee) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[O:15][N:14]=1.O>CCOC(C)=O>[CH3:12][C:13]1[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc(N)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-bromo-2-nitroaniline (1 g, 4.6 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (2 g, 9.2 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (12 ml) and water (6 ml). To the above mixture were added PEPPSI-Ipr (312 mg, 0.46 mmol) and CsCO3 (4.5 g, 13.8 mmol). The reaction mixture was heated at 120° C. for 30 min. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with flash column chromatography (50% EtOAc/Hexane) to afford 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.S(OC)(O[CH3:23])(=O)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:23][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Reactant: COS(=O)(=O)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(N2CCCCCC2=O)CC1(C)C
Temperature: 80 °C

Procedure:
A solution of 63.0 g (0.25 mole) of N-(2,2,6,6-tetramethylpiperidin-4-yl)-epsilon-caprolactam, prepared in Example 1, in 150 ml of toluene is added to a flask fitted with a reflux condenser, stirrer and thermometer. To this solution is then added a second solution of 28.5 ml (0.30 mole) of dimethyl sulfate in 100 ml of toluene. The mixture is heated for one hour at 80° C. and then 50 ml of concentrated ammonium hydroxide is added.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:15][N:16]([C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CNC1c2ccccc2CCC1N1CCCC1
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 54.9 %

Procedure:
Using the procedure of Step C of Example 1, 2.3 g of 1-naphthylacetic acid and 2 g of the product of Step B of Example 1 were reacted to obtain 5.3 g of crude product which was purified by chromatography on silica (methylene chloride 9-methanol 1). After crystallization from ethyl ether, 1.9 g of product melting at 117° C. were obtained which was crystallized from isopropyl ether to obtain 1.1 g of the expected product melting at 125° C.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1.[CH3:23][C:24]1[C:25](B(O)O)=[CH:26][S:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16]([C:25]3[C:24]([CH3:23])=[CH:28][S:27][CH:26]=3)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1
Reactant: Cc1cscc1B(O)O
Reactant: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cscc2C)cc2c(C)nc(N)nc21
Temperature: 100 °C
Yield: 54.5 %

Procedure:
A 3:1 solution of dioxane and water (4 mL) was added to a flask charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.140 g, 0.495 mmol) from above, 4-methylthiophene-3-boronic acid (0.140 g, 0.989 mmol), Pd(PPh3)4 (0.057 mg, 0.050 mmol), and K2CO3 (0.205 g, 1.48 mmol). The flask was flushed with nitrogen and fitted with a reflux condenser and heated to 100° C. After 12 hours the reaction was cooled to room temperature and diluted with ethyl acetate (70 mL) and washed with water. The aqueous phase was separated and washed with an additional amount of ethyl acetate (70 mL). The organic phases were combined and washed with brine, separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (1:1 methylene chloride:ethyl acetate) to give 2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.081 g, 55% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.19 (m, 3H), 4.32 (q, J=8.0 Hz, 2H), 2.52 (s, 3H), 2.11 (bs, 3H), 1.19 (t, J=8.0 Hz, 3H); MS (EI) for C15H16N4OS: 301.1 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C[O-].[K+].[C:18](OC)(=[O:24])[CH2:19][C:20](OC)=[O:21]>CO>[OH:24][C:18]1[N:10]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:5][CH:6]=2)[NH:9][C:20](=[O:21])[CH:19]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=c1cc(O)nc(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Trifluormethylbenzamidine hydrochloride (22.4 g, 0.1 mol, from example 41) is added to a solution of potassium methylate (0.22 mol) in anhydrous methyl alcohol (65 mL) and stirred for 15 minutes at ambient temperature. Dimethyl malonate (12.6 mL, 0.11 mol) is added and the mixture is heated to reflux for 4 hours. After cooling, the resulting suspension is diluted with methyl alcohol (50 mL).
Reaction SMILES: [ClH:1].[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].S(Cl)([Cl:30])=O>>[ClH:30].[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:1])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reaction time: 20 h

Procedure:
A mixture of 1.00 g of 4-(n-hexadecylamino)benzoic acid hydrochloride and 5.00 ml of thionyl chloride is allowed to stand at ambient temperature for 20 hours and then is concentrated in vacuo to yield 4-(n-hexadecylamino)benzoyl chloride hydrochloride as an orange solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:45]OC1C=C(C=CC=1)CCN>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][CH2:27][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:45]=1)=[O:24])=[CH:17]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1cccc(CCN)c1
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Product: COc1cccc(CCNC(=O)c2cc3cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(O)c(CO)c4)ccc3[nH]2)c1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 3-methoxyphenethylamine to give the title compound as a pale brown foam.