Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:5]2
Reactant: Brc1cccnc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Brc1ccc2c(ccn2-c2cccnc2)c1

Procedure:
5-Bromo-N-(3-pyridyl)indole is prepared from 5-bromoindole and 3-bromopyridine using methodology described in the previous examples.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:43][C@@H:44]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C@@H:45]([OH:56])[CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([F:55])([F:54])[F:53].CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:43][C@@H:44]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C@@H:45]([OH:56])[CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([F:55])([F:53])[F:54])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(F)(F)F
Reaction time: 0.08 h

Procedure:
A stirred solution, cooled to 0° C., of 4.81 g (22.13 mmol) of N-(tert-butoxycarbonyl)-L-valine and 3.29 g (24.35 mmol) of HOBT in 40 ml of anhydrous dichloromethane was treated with 5.29 g (25.65 mmol) of DCC and stirred for 5 min. A solution of 3.70 g (20.12 mmol) of the compound from Example 2 and 8.85 ml (80.48 mmol) of N-methylmorpholine in 30 l of dichloromethane was then added dropwise. The cooling bath was removed and the reaction solution was stirred at room temperature for 2 h. The end of the reaction was determined by thin layer chromatography. The resulting urea was removed by filtration, the filtrate was concentrated in vacuo, and the crude product was purified by chromatography on 400 g of silica gel (dichloromethane: methanol). 6.89 g (68% of theory) of the title compound were obtained as a colourless foam. Rf = MS (DCI, NH3): m/e=503 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1Br.[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]1>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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1[C:21]1[CH2:22][CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19][CH:20]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: Nc1ccc(CC(=O)NCCCO)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2N)CC1

Procedure:
The title compound was prepared from 2-(4-amino-3-bromo-phenyl)-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step), 4,4-dimethylcyclohexen-1-yl boronic acid and Pd(PPh3)4 according to the procedure in Example 1, step (e). Mass Spectrum (ESI, m/z): Calcd. for C19H28N2O2, 317.2 (M+H). found 317.1.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([CH2:9][N:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]2=[O:17])[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:9][CH:6]2[CH2:8][CH2:7]2)[C:11](=[O:17])[CH:12]=1
Reactant: O=c1cc(O)ccn1CC1CC1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: O=c1cc(Br)ccn1CC1CC1
Temperature: 110 °C
Yield: 92.8 %

Procedure:
Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a solution of intermediate D2 (1.42 g, 8.6 mmol) in DMF (140 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were dried (Na2SO4) and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D3 (1.82 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (300 mg, 1.25 mmol) and tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate (500 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethylamine (0.43 mL, 2.50 mmol). The reaction was heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is then partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 160 mg (32% yield) of the desired product: MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCN
Solvent: O
Solvent: CCO
Product: CCNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 77 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 20.8 g of ethylamine are added as 33% solution in water. The reaction mixture is refluxed for 2 hours and is then evaporated to dryness. The precipitate obtained is taken up in 100 ml of water. After 1 hour's stirring, the mixture is filtered on sintered glass. The precipitate is recrystallized from 25 ml of acetonitrile. 8.10 g of 2-amino-4-ethylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][CH:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C>C(#N)C>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][CH:8]([NH2:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(CC(C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Solvent: CC#N
Solvent: CCNCC
Product: CC(C)(C)OC(CC(N)C=O)=NNC(N)=O
Reaction time: 2 h

Procedure:
(3S) 3-(1-Fluorenylmethoxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (4; 226 mg, 0.5 mmol; prepared in a similar manner as the benzyloxycarbonly analog described in Graybill et al. Int. J. Protein Res., 44, pp. 173-82 (1994)) was dissolved in 10 ml of acetonitrile (20 ml) and diethylamine (2 ml) was added to the solution. The reaction was stirred for two hours, concentrated in vacuo, the resulting dissolved in acetonitrile and concentrated in vacuo again to give (3S) 3-amino-4-oxobutyric acid tert-butyl ester semicarbazone. A 5° C. solution of the semicarbazone and 3 (188 mg, 0.424 mmol) in methylene chloride/DMF (6 ml of 1:1) was treated with 1-hydroxybenzotriazole (HOBt; 57 mg, 0.424 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC; 115 mg, 0.6 mmol) and the reaction was stirred at room temperature for 16 hr. The reaction was diluted with ethyl acetate (100 ml) and washed with water, aqueous saturated NaHCO3 and aqueous saturated NaCl, dried over dried over anhydrous Na2SO4 and concentrated in vacuo. Chromatography (SiO2, 5% ammonium hydroxide/5% methanol/methylene chloride eluent) gave 250 mg of 5
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[NH2:13][C:14]1[C:26]([Br:27])=[CH:25][C:17]2[C:18]([C:21]([NH:23][CH3:24])=[O:22])=[CH:19][O:20][C:16]=2[CH:15]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:39](=[O:41])[CH3:40]>C1COCC1>[C:39]([C:19]1[O:20][C:16]2[CH:15]=[C:14]([NH2:13])[C:26]([Br:27])=[CH:25][C:17]=2[C:18]=1[C:21]([NH:23][CH3:24])=[O:22])(=[O:41])[CH3:40]
Reactant: CON(C)C(C)=O
Reactant: CNC(=O)c1coc2cc(N)c(Br)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(C(C)=O)oc2cc(N)c(Br)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of diisopropylamine (3.76 g, 37.1 mmol) in THF (25 mL) was slowly added a solution of n-BuLi (2.5 mol/L in hexane) (16.5 mL, 40.5 mmol) under N2 at −78° C. and the resulting solution was stirred at −78° C. for 30 minutes. A solution of compound 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (2 g, 7.43 mmol) in THF (50 mL) was slowly added to the fresh lithium diisopropylamide at −78° C. and stirred for another one hour. To the resulting mixture was added N-methoxy-N-methylacetamide (3.83 g, 37.16 mmol) at −78° C. and stirred for another one hour. The reaction was quenched with saturated NH4Cl at −78° C. and the mixture was slowly warmed to room temperature. Water was added and the mixture extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (700 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 10.00 (s, 1H), 8.76 (s, 1H), 6.86 (s, 1H), 4.54 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 311/313.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1)(=[O:3])[CH3:2].[CH2:35]([N:37]([CH2:41][CH3:42])[C:38](Cl)=[O:39])[CH3:36]>C1COCC1>[C:1]([O:4][C@@H:5]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:38]([N:37]([CH2:41][CH3:42])[CH2:35][CH3:36])=[O:39])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cncc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Temperature: 110 °C

Procedure:
1 g (2.02 mM) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 0.5 ml (3.95 mM) of diethylcarbamoyl chloride, 50 mg (0.06 mM) of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane and 15 ml of THF are placed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 110° C. for 30 minutes by microwaves. The cooled reaction mixture is filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using pure dichloromethane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. After washing with an ether/isopropyl ether mixture, the brown solid obtained is used directly in the deacetylation reaction described in Example 160.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:4]([CH3:11])[N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1nc(N)c(C#N)nc1Br
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: Cc1ccccc1
Product: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.7 grams (0.008 mole) of 2-amino-3-cyano-5-bromo-6-methylpyrazine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-5-[3,5-di(trifluoro-methyl)phenyl]-6-methylpyrazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:27][C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(NC(C)C)(C)C.[Cu](I)I>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:31]#[C:30][C:28]([OH:32])([CH3:29])[CH3:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1

Procedure:
A suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and 2-methyl-3-butyn-2-ol (110 mg, 1.3 mmol) in dimethylformamide (20 ml) and diisopropylamine (5 ml) are stirred in the presence of bis triphenylphosphine palladiumdichloride (20 mg), triphenylphosphine (20 mg) and copper iodide under a nitrogen atmosphere for 16 hours. After an aqueous work-up the residue is purified by chromatography (eluent: 1:2 mixture of ethyl acetate/hexane) to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(3-hydroxy-3-methyl-1-butynyl)-phenyl]-amine, m.p. 262–263° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+:15]>CO>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.[Na+:15]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-trifluoromethyl benzoic acid (0.100 g, 0.239 mmole) in methanol (2.0 mL), is added sodium hydroxide (0.093 g, 0.287 mmole) and stirred at room temperature for 2 hours. The mixture is concentrated to dryness in vacuo to give sodium 4-trifluoromethyl-benzoate as a white solid. It is then mixed with NH4OAc (8.329, 107.9 mmole) in glacial acetic acid (500 mL) and heated at 100° C. for 16 hours. After removed the solvents on rota-vapor, the residue is partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate (300 mL). Extracted the aqueous layer with ethyl acetate (300 mL) one more time. The combined organic is ish with brine (3×500 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography on silica gel column, gradient elute with 0 to 10% ethyl acetate in hexane and concentrated to provide the titled compound as a white solid. Mass [EI+] 300 (M++H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH2:12][OH:13].[C:17]([O:21]C)(=[O:20])[CH:18]=[CH2:19].CC(C)([O-])C.[K+].O1CCCC1.C(O)(C)(C)C.Cl>>[CH2:12]([O:13][CH2:19][CH2:18][C:17]([OH:21])=[O:20])[CH:11]=[C:10]([CH2:9][CH2:8][CH:7]=[C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:15])[CH3:14]
Reactant: C=CC(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCOCCC(=O)O

Procedure:
All-trans-farnesol was reacted with methyl acrylate in the presence of one equivalent of 0.1 equivalent of potassium-tert butoxide/tetrahydorfuran/t-butanol for three hours at room temperature. The solution was acidified with 0.1N HCl, evaporated to dryness, and purified by thin layer chromatography on silica. The free acid was prepared by treatment of the ester with potassium hydroxide in methanol. The product showed the anticipated nmr and infrared spectra.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:6](=[N:7][C:8]3[C:9]=2[CH2:11][CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1([CH3:23])[C:10]2[C:6](=[N:7][C:8]3[C:9]=2[CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCCC2=NC3=C(OCc4ccccc4)C=CCC3=C21
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCC(C)(C)C3=C21
Yield: 50.3 %

Procedure:
Using the procedure of Example 9, the alkylation of 7.7 g of 1,2,3,4-tetrahydro-1,1-dimethyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 58 was reacted with 5.48 g of 1-bromooctane to produce 5.3 g (50.5%) of 1,2,3,4-tetrahydro-1,1-dimethyl-6-phenylmethoxy-9-octyl-9H-dibenzo-[b,d]pyrrole as an orange oil after chromatographic purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:40]([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH:29]([CH3:40])[CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OC(C)C)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Yield: 71.9 %

Procedure:
A mixture of Example 1 (0.400 g, 0.743 mmol) and K2CO3 (0.400 g, 2.89 mmol) in isopropanol (10 mL) was heated at 120° C. for 1 h with microwave irradiation. The solids were removed by filtration and washed with THF. The filtrate was concentrated to dryness. The residue was stirred in water (15 mL) and the remaining solids were collected and crystallized from MeCN to provide N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide, (0.295 g, 71.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 10.58 (s, 1H), 8.29 (dd, J=12.6, 7.2 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.50-7.49 (m, 3H), 7.35 (t, J=8.7 Hz, 2H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.85 (m, 1H), 2.03 (s, 3H), 1.31 (d, J=6.0 Hz, 6H); MS (ESI) m/z: 553.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Mg]Br)C.[CH:10](=[O:17])[CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][CH:2]([OH:5])[C:3]#[C:4][CH:10]([OH:17])[CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]
Reactant: CCC=CCCC=O
Reactant: C#CC(C)O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC=CCCC(O)C#CC(C)O

Procedure:
But-3-yn-2-ol was added into a solution of ethyl magnesium bromide (EtMgBr) in tetrahydrofuran (THF). Hept-4-enal was then dropped into the mixture at room temperature and aged for 2 hours. The rush over process provided the product undec-8-en-3-yne-2,5-diol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15]CC3CCOCC3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:23]([OH:26])([CH3:25])C>C(#N)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:15])=[C:7]([NH:12][CH2:11][CH:2]3[CH2:25][CH2:23][O:26][CH2:4][CH2:3]3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCOCC1
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(NCC2CCOCC2)cnc2cc(Br)ccc12
Reaction time: 2 h

Procedure:
7-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (20 g, 55 mmol) was dissolved in a mixture of acetonitrile (500 mL) and isopropyl alcohol (50 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 2 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 7-bromo-N-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine which was carried forward without further purification assuming quantitative yield.
Reaction SMILES: [C:1]([O:20][CH:21]1[CH2:24][N:23](C(=O)C)[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.[ClH:36]>CO.C(OCC)(=O)C>[ClH:36].[C:1]([O:20][CH:21]1[CH2:22][NH:23][CH2:24]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(C(OC2CNC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In 88 mL of methanol was suspended 22.0 g of 1-[3-(trityloxy)-1-azetidinyl]-1-ethanone, followed by adding thereto 66 mL of a 5 mol/L aqueous sodium hydroxide solution, and the resulting mixture was refluxed for 9 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and 110 mL of water and 220 mL of ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The oil thus obtained was dissolved in 154 mL of ethyl acetate, and to the resulting solution was added 25 mL of a 2.95 mol/L dried hydrogen chloride-ethyl acetate solution, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 13.7 g of 3-(trityloxy)azetidine hydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCC=O
Reactant: CCCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Product: CCCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, ethyl 4-(3-n-heptyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 113, 0.024 g, 0.05 mmol) was reacted with propionaldehyde to afford 0.026 g (100%) of the title compound as a yellow oil.