Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][OH:18])=[O:10])=[CH:5][CH:4]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:18][CH2:17][C@@H:12]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:11]2[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CO)cc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol (64 g: 227.6 mmole) in pyridine (350 ml), p-toluenesulfonyl chloride (48 g) is added. The mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water, dilute hydrochloric acid and aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (60 g). NMR δ(CDCl3) ppm: 2.0 to 2.4(m, 2H), 2.44(s, 3H), 3.3 to 3.7(m, 2H), 3.82(s, 3H), 3.9 to 4.6(m, 4H), 4.8 to 5.1(m, 2H), 6.88(d, J=8.6 Hz, 2H),7.2 to 7.4(m, 4H), 7.6 to 7.8(m, 2 H). IR ν (CHCl3) cm-1 : 3446, 1693.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[C:8]2[CH3:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(C)C)c(Cc3ccc(F)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1c(Cc2ccc(F)cc2)c(OC(C)C)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
A solution of [8-chloro-3-(4-fluorobenzyl)-2-isopropoxy-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.020 g), methanol (1.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.25 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (30% to 90% of organic modifier) gave title compound as a white solid, 0.0085 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:27])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[N:29]1([C:38](=N)[NH2:39])C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[Cl:26][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:27])[C:20]=1[S:19][C:13]1[S:12][C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH2:39])=[NH:29])=[CH:7][CH:6]=2)=[O:10])=[CH:15][C:14]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Reactant: N=C(N)n1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N=C(N)Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Temperature: 60 °C
Yield: 9.2 %

Procedure:
To a solution of N-(4-aminophenyl)-5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamide (0.2 g, 0.45 mmol) and 1H-benzo[d][1,2,3]triazole-1-carboximidamide HCl salt (0.18 g, 0.91 mmol) in acetonitrile (4 mL) was added triethylamine (0.13 mL, 0.91 mmol). After the addition, the resulting reaction mixture was heated at 60° C. for 24 hours. After this time, the reaction mixture was concentrated and purified by reverse phase HPLC to afford the titled product as a solid (20 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.66 (1H, s), 9.68 (1H, m), 9.01 (2H, m), 8.74 (1H, s), 7.73 (2H, m), 7.39 (4H, m), 7.25 (3H, m), 7.12 (2H, dd). MS m/z: 483.06, 485.06 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=1)#[N:2].[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:30][CH2:29][C@@H:28]([NH:27][C:16]([C:14]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=1)=[O:17])[CH3:31]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccccc3CO)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3ccccc3CO)c2)c(C#N)c1
Temperature: 25 °C

Procedure:
A reaction vial was charged with 2-Cyano-2″-hydroxymethyl-4-methyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (50.00 mg, 0.1456 mmol), (2S)-2-aminopropan-1-ol (13.12 mg, 0.1747 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (110.7 mg, 0.2912 mmol), N,N-diisopropylethylamine (0.06341 mL, 0.3640 mmol) and N,N-dimethylformamide (5.0 mL, 64 mmol) and the reaction stirred at room temperature over night. The reaction mixture was then purified by prep HPLC to get the compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1>>[ClH:15].[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1ccc(C)c(C)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(C)c(C)c1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reaction of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethyl-phenyl)-ethyl]-amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1ccccc1C(C)=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (1.0 g, 7.3 mmol) and methyl bromoacetate (0.70 mL, 7.3 mmol) were combined in acetone (20.0 mL) with potassium carbonate (2.0 g, 15 mmol) and was stirred at room temperature. The reaction mixture was stirred for 18 h, diluted with EtOAc and filtered to remove the solids. The organic layer was concentrated to give the sub-title compound as a clear oil (1.5 g, 100%). LCMS calc. for C11H13O4 (M+H)+: m/z=209.1. found: 209.1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[CH3:25][C@H:26]1[O:31][C@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([N:28]5[CH2:27][C@@H:26]([CH3:25])[O:31][C@H:30]([CH3:32])[CH2:29]5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C2CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)C[C@@H](C)O1

Procedure:
To a solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (380 mg, 1.12 mmol) in toluene (10 mL) under nitrogen was added trans 2,6-dimethylmorpholine (155 mg, 1.34 mmol, 1.23 eq). The trans 2,6-dimethylmorpholine isomer was obtained by spinning band distillation of the commercially available mixture of 2,6-dimethylmorpholines. The solution was heated to reflux passing the solvent through 3 A molecular sieves in a modified Dean Stark arrangement. After 2 h, the solvent was removed, replaced with tetrahydrofuran (1.0 mL), and cooled to 0° C. Excess hydrogen chloride gas was bubbled into the solution and then purged with nitrogen. The reaction was warmed to room temperature and a solution of sodium cyanoborohydride (210 mg, 3.35 mmol, 9 eq) in methanol (0.50 mL) was added. A significant amount of gas was evolved. The reaction was stirred for 18 h and quenched with 2.5 N NaOH (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography over silica gel (40 mL, eluent: 30% ethyl acetate in hexane) to yield the title compound as a white solid (371 mg, 76%), mp 237° C. (dec); NMR (CDCl3, 300 MHz) 7.23 (dd, J=5.9, 1.6 Hz, 1H), 7.12 (m, 4H), 6.92 (m, 3H), 4.22 (s, 1H), 3.97 (m, 2H), 3.67 (t, J=6.3 Hz, 1H), 3.58 (t, J=6.2 Hz, 1H), 3.32 (s, 2H), 2.52 (dd, J=11.0, 3.1 Hz, 2H), 2.19 (m, 4H), 1.71 (m, 3H), 1.20 (d, J=6.4 Hz, 6H) MS (CI, CH4) m/z 437 (M+1,100), 439 (34), 465 (M+29,15) The free base was dissolved in diethyl ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 237°-240° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][C:29](O)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].C1CCN2C(=NCCC2)CC1>CN(C)C=O.O>[CH2:32]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:27][CH2:28][C:29]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:30])[CH:17]=2)[N:12]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)O)cc23)cc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)NS(C)(=O)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetic acid (0.25 g, 0.52 mmol) in N,N-dimethylformamide (5 ml) was added di(N-succinimidyl) carbonate (0.42 g, 2.6 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added methanesulfonamide (0.25 g, 2.6 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.40 ml, 2.6 mmol), and the mixture was stirred at 100° C. for 5 hrs. The reaction mixture was cooled to room temperature and water was poured thereinto. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from n-hexane-diisopropyl ether to give tert-butyl [(2-isobutyl-4-(4-methylphenyl)-6-{2-[(methylsulfonyl)amino]-2-oxoethoxy}quinolin-3-yl)methyl]carbamate (0.29 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[CH:6][CH:7]=1
Reactant: CCOCc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCc1ccc(CCl)cc1

Procedure:
[4-(Ethoxymethyl)phenyl]methanol (1.52 g) synthesized in Reference Example 39 was dissolved in carbon tetrachloride (20 mL), triphenylphosphine (2.64 g) was added thereto, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in hexane, the insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1) to give the title compound (1.07 g) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH3:9][N:10]([CH3:12])[CH3:11]>C(O)C>[Br-:1].[CH3:9][N+:10]([CH3:12])([CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:10]([CH3:12])([CH3:11])[CH3:9].[Br-:1]
Reactant: BrCCCCCCBr
Reactant: CN(C)C
Solvent: CCO
Product: C[N+](C)(C)CCCCCC[N+](C)(C)C
Product: [Br-]

Procedure:
37.38 g of 1,6-dibromohexane (purity=96%) and 82.35 g of trimethylamine solution (31-35% by weight in ethanol) are added to a 500 ml flask, and the necessary ethanol is immediately added for obtaining a suitable mixture of the different products that have been added while they are homogenised by magnetic stirring. The resulting mixture is kept at room temperature with constant stirring for 48 hours, and the solid that is formed is recovered by means of filtration and is thoroughly washed with ethyl acetate and diethyl ether. The white solid obtained is dried at room temperature for 12 hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].CN(C)C=O.[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COC(C)(C)C.O>[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCCOCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a 3-L reaction vessel was charged and stirred potassium carbonate (152 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-chloropropyl phenylmethyl ether (96.4 g) at 90° C. for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter.
Reaction SMILES: [O:1]1CCO[CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=2)([CH3:17])[CH3:16])=[N:12][CH:13]=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.C1C(=O)N([Br:50])C(=O)C1>C(OCC)(=O)C>[Br:50][CH2:3][C:2]([C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=2)([CH3:17])[CH3:16])=[N:12][CH:13]=1)=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C1COCCO1
Reactant: CC(C)(Nc1ncc(Br)cn1)c1ncccc1Cl
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CC(C)(Nc1ncc(C(=O)CBr)cn1)c1ncccc1Cl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirring solution of dioxane (50 mL, degassed) was added 5-bromo-N-(2-(3-chloropyridin-2-yl)propan-2-yl)pyrimidin-2-amine (3.0 g, 12 mmol), Cl2Pd(PPh3)2 (0.65 g, 1.2 mmol), and tributyl(1ethoxyvinyl)tin (2.66 mL, 13.8 mmol). The reaction was heated to 90° C. and stirred for 2 h. The reaction was then concentrated, followed by the addition of EtOAc (100 mL) and potassium fluoride (50 mL of a saturated aqueous solution). The mixture was stirred for 10 min and then filtered through a pad of celite. The filtrate was concentrated and then dissolved in THF (20 mL) and water (20 mL). NBS (4.9 g, 27.6 mmol) was then added, and the reaction was stirred for 20 min at rt. The reaction mixture was poured into ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to afford 1.5 g of 2-bromo-1-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)ethanone as a white powder.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[C:31]([CH3:32])=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:33].O>ClCCl>[CH3:21][O:22][C:23]1[C:24]([CH3:33])=[CH:25][C:26]([C:27]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])=[CH:30][C:31]=1[CH3:32]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1cc(C)c(OC)c(C)c1)C(=O)OCC
Reaction time: 2 h

Procedure:
58.4 g of diethyl aminomalonate hydrochloride were suspended in 300 ml of dichloromethane, and 115 ml of triethylamine were added with ice cooling. At 0° C., 54.8 g of 4-methoxy-3,5-dimethylbenzoyl chloride in 250 ml of dichloromethane were then added dropwise. After 2 hours at 0° C., 100 ml of water were added dropwise, and the aqueous phase was separated off and extracted with 200 ml of dichloromethane. The combined organic phases were extracted first with 2M aqueous hydrochloric acid and then with water, dried over sodium sulfate, filtered and concentrated. The residue was triturated with methyl tert-butyl ether, filtered off with suction and dried under reduced pressure. This gave 89.3 g (96%) of the title compound which was reacted further without any further purification.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[CH:28]=[N:27]1>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:35][C:32]5[CH:33]=[C:34]6[C:29]([CH:28]=[N:27][N:26]6[CH3:25])=[CH:30][CH:31]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Reactant: Cn1ncc2ccc(N)cc21
Product: Cn1ncc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)CC6CC6)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 1-methyl-1H-indazol-6-ylamine (50.0 mg, 0.340 mmol) at 105° C. for 168 h to afford the titled compound. Yield of TFA salt: 11 mg (10%) of brown powder; LC/MS: 459 (M+H); HPLC: 97% pure, RT=3.29 min; 1H NMR: (DMSO, δ) 9.74 (s, 1H), 9.10 (s, 1H), 8.58 (d, J=7.7, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.84 (d, J=7.9, 1H), 7.82 (s, 1H), 7.78 (t, J=7.9, 1H), 7.56 (d, J=8.7, 1H), 7.23 (d, J=8.7, 1H), 7.20 (d, J=4.9, 1H), 6.95 (d, J=4.9, 1H), 3.69 (s, 3H), 3.22 (d, J=7.3, 2H), 0.78 (m, 1H), 0.33 (m, 2H), −0.01 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[OH-].[NH4+:5].[Cl-].[NH4+].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[NH2:5][C:8]1([C:1]#[N:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CC1(N)CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Sodium cyanide (23.7 g, 482 mmol) was added to a solution of ammonium hydroxide (28%, 122 mL, 965 mmol) and ammonium chloride (28.4 mL, 531 mmol) in water (100 mL). Cyclohexanone (50 mL, 482 mmol) was added over 5 min. The reaction was heated at 60° C. for 6 h, then was allowed to cool to rt and stir overnight. The mixture was transferred to a separatory funnel and was washed with dichloromethane (3×200 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, eluted with 20% hexanes/ethyl acetate) provided 1-aminocyclohexanecarbonitrile as a clear oil (49.5 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:2]=1[N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([OH:6])=[O:5]
Reactant: CCOc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCNC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCN(C)c1cc(OCC)c([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 24.5g 2-chloro-4-ethoxy-5-nitrobenzoic acid, 22.7g methyl tetradecylamine (distilled) and 35.0 ml triethylamine were heated on a steam bath for 5 hours and then poured into two liters of water and made acid with HCl. The reaction product was filtered and washed with water, and recrystallized twice from methanol/water.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]([NH:9]C(OC(C)(C)C)=O)[C:6]([OH:8])=[O:7])[CH3:3].[CH2:17]1[CH:21]2[CH:22]3C(=O)N(O)C(=O)[CH:23]3[CH:18]1[CH:19]=[CH:20]2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[NH2:9][C@H:5]([C:6]([O:8][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])[CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
pTos (21.6 g) was dissolved in DMF (100 ml), and the solution was cooled with ice. TEA (7.7 ml) and Boc-D-Leu-ONB (prepared from Boc-D-Leu--OH. H2O (12.5 g), HONB (9.86 g) and DCC (11.4 g) were added thereto, followed by stirring overnight. The resulting DCU was separated by filtration, and the filtrate was concentrated to obtain a residue. The residue was dissolved in AcOEt, and the resulting solution was washed with 4% aqueous NaHCO3 and 10% aqueous citric acid. After washing with water, the solution was dried with Na2SO4 and concentrated. Ether was added to the resulting residue to separate out a precipitate, which was collected by filtration.
Reaction SMILES: C12CC3CC(CC(C3)C1CC(O)=O)C2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH:33]1[CH2:42][N:43]=[C:44]=[O:45])[CH2:39]2.[F:46][C:47]1[C:48](=[O:54])[NH:49][C:50](=[O:53])[NH:51][CH:52]=1>N1C=CC=CC=1>[CH:34]12[CH2:40][CH:38]3[CH2:37][CH:36]([CH2:41][CH:32]([CH2:39]3)[CH:33]1[CH2:42][NH:43][C:44]([N:51]1[CH:52]=[C:47]([F:46])[C:48](=[O:54])[NH:49][C:50]1=[O:53])=[O:45])[CH2:35]2
Reactant: O=C=NCC1C2CC3CC(C2)CC1C3
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C(O)CC1C2CC3CC(C2)CC1C3
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC(C2)CC1C3)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 2-adamantylacetic acid and diphenyl phosphoryl azide in dry pyridine provided a solution comprising 2-adamantylmethyl isocyanate [I.R.: 2260 cm-1 ], which was reacted with 5-fluorouracil to provide 1-[N-(2-adamantylmethyl)carbamoyl]-5-floururacil substantially in the similar method to that of Example 45.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.[CH2:13](B(O)O)[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCB(O)O
Reactant: O=Cc1cc2cc(Br)ccc2[nH]1
Product: CC(C)CCc1ccc2[nH]c(C=O)cc2c1
Yield: 37.1 %

Procedure:
5-Isopentyl-1H-indole-2-carbaldehyde was synthesized as in Example 3.1 using 5-bromo-1H-indole-2-carbaldehyde (300 mg, 1.34 mmol) in place of 5-bromo-2-formylfuran and isopentylboronic acid (256 mg, 2.21 mmol) in place of hexylboronic acid to give 5-isopentyl-1H-indole-2-carbaldehyde (107 mg, 37%). Used without further characterization.