Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]([F:23])([F:22])[CH:17]([OH:21])[C:18](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:15][C:16]([F:23])([F:22])[CH:17]([C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:7])=[CH:8][C:9]=2[N:10]=1)[OH:21]
Reactant: N#Cc1cc(N)c(N)cc1C(F)(F)F
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Diamino-2-trifluoromethyl-benzonitrile (4.14 g; 20.6 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (4.50 g; 31.2 mmoles) were suspended in 6N HCl (7 mL; 42 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (5.19 g; 62.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a dark brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=1.N([O-])=O.[Na+].C(Cl)Cl.[BrH:23]>[Cu]Br>[Br:23][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2ncccc2F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Br)cc1-c1ncccc1F

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylamine was subjected to reaction with sodium nitrite, in hydrobromic acid in the presence of copper(I) bromide, according to the method of Example 23. 2-(5-Bromo-2-fluorophenyl)-3-fluoropyridine was obtained by chromatography (silica gel, CH2Cl2) as a pink solid: MS (ES+) m/z 270, 272 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10].Cl[C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:15]1[C:14]([N+:21]([O-:23])=[O:22])=[C:13]([NH:1][C@@H:2]2[C@@H:7]3[O:8][C@@H:4]([CH2:5][CH2:6]3)[C@@H:3]2[C:9]([NH2:11])=[O:10])[C:18]([Cl:19])=[CH:17][N:16]=1
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2CC[C@@H]1O2
Temperature: 60 °C
Yield: 100.7 %

Procedure:
(1S,2R,3S,4R)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxamide (15) (170 mg, 0.67 mmol), 4,5-dichloro-3-nitropyridin-2-amine (127 mg, 0.6 mmol), DIPEA (5.5 eq) were taken in IPA and heated at 60° C. for 15 h when a yellow precipitate appeared. The precipitate was filtered, washed well with IPA and dried to afford the desired product, (198 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Clc1ccnc(Cl)n1
Product: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1

Procedure:
The title compound was prepared from 2,4-dichloropyrmidine and 1-ethynyl-4-fluorobenzene using methods analogous to those described in Example 2 (65%). TLC (25% EtOAc/hexanes): Rf=0.21. mp 125-126° C. IR: 3049 (w), 2210 (w), 1559 (s). 1H NMR (CDCl3): 8.61 (d, J=5.0 Hz, 1H), 7.70-7.60 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 7.13-7.06 (m, 2H). 13C NMR (CDCl3): 163.99 (d, JC-F=252 Hz), 161.86, 159.66, 153.39, 134.96 (d, JC-F=8.6 Hz), 121.77, 116.96 (d, JC-F=3.4 Hz), 116.40 (d, JC-F=22 Hz), 95.27, 85.89. Anal. Calcd for C12H6ClFN2: C, 61.95; H, 2.60; N, 12.04. Found: C, 62.15; H, 2.83; N, 12.00.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(F)(F)F)c1C
Yield: 89 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-benzoic acid (Apollo, 1 g, 4.90 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.5 mL) and the resulting mixture was heated to reflux overnight. The cooled reaction mixture was concentrated and diluted with water (25 mL) and a saturated sodium bicarbonate solution (25 mL). The mixture was extracted with ethyl acetate (50 mL), the organic phases combined, washed with water and dried over magnesium sulfate. The mixture was filtered and evaporated to give 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol, 89%); 1H NMR (300 MHz, CDCl3) δ ppm 2.65 (s, 3H), 3.94 (s, 3H), 7.35 (t, J=7.85 Hz, 1H), 7.72-8.01 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:14]3[N:15]=[C:16]([S:27][CH3:28])[C:17]([N:18]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:19][CH:20]4[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.C([Sn]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:20]1([CH2:19][N:18]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:17]2[C:16]([S:27][CH3:28])=[N:15][N:14]3[C:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([C:44]5[S:45][CH:46]=[CH:47][N:48]=5)=[CH:3][C:4]=4[O:29][CH3:30])=[CH:10][CH:11]=[CH:12][C:13]=23)[CH2:22][CH2:21]1
Reactant: COc1cc(Br)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nccs2)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
After dissolving N-[7-(4-bromo-2-methoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (45 mg) in toluene (0.60 mL), tributylstannylthiazole (52 mg) and tetrakis (triphenylphosphine)palladium(0) complex (9 mg) were added, the mixture was heated and stirred at 120° C. for 2 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to obtain the title compound (30 mg) as white crystals.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:10]=[C:11]([C:12]([F:14])([F:13])[F:15])[C:6]3=[N:5][CH:4]=2)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (310 mg, 0.88 mmol) and 5-Bromo-2,4,-difluorobenzenesulfonamide (226 mg, 0.83 mmol) according to general procedure II. Obtained as an off-white solid (56 mg, 12%). MS (ISP) 546.2 [(M+H)+]; mp 306–307° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.C(N(CC)CC)C>O1CCOCC1.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>[C:42]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a well degassed mixture of 7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.101 g, 0.188 mmol) and Bis(triphenylphosphine)palladium(II) chloride (0.018 g, 0.026 mmol) in 1,4-dioxane (2.0 mL) in a sealed tube was added tributyl(1-ethoxyvinyl)stannane (0.148 mL, 0.450 mmol) followed by triethylamine (0.052 mL, 0.375 mmol). The resulting mixture was evacuated and charged with nitrogen (2×), immersed in an oil bath at 100° C., and stirred overnight. The mixture was diluted with ethyl acetate, filtered through a pad of CELITE®, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 N aqueous hydrochloric acid (2 mL) for 2 h. The solution was concentrated under reduced pressure, and the residue was suspended in water. The pH was adjusted to ˜6 with 1 N sodium bicarbonate, and the suspension was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate and hexane (50%-62%-75%-88%) afforded 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.051 g, 0.102 mmol, 54% yield) as a pale yellow solid. LC/MS M+1=502.1.
Reaction SMILES: [CH3:1][CH2:2][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][CH2:17][CH2:18][OH:19].[CH3:20][O:21][C:22]([CH3:24])=[CH2:23]>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:20][O:21][C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: C=C(C)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(C)(C)OC

Procedure:
2-methoxy-2-(octadecyloxy)propane was prepared by reacting stearic alcohol (0.025 mole) with 2-methoxypropene (4 equivalents) for 2 hours at 20° C. in the presence of one drop of phosphoryl chloride (POCl3) then adding 5 drops of triethylamine and distilling the excess enol ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[NH:28][CH2:29][CH2:30][N:31]=2)=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C2=NCCN2)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(Cl)c(-c2ncc[nH]2)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 2-[4-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-5-methyl-pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (45 mg, 0.1 mmol), Dess-Martin periodinane (80 mg, 0.2 mmol) in DMSO (1 mL) was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (20 mL) and washed with water (3×5 mL). The organic layer was dried (Na2SO4), filtered, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give 2-[4-chloro-3-(1H-imidazol-2-yl)-5-methyl-pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone as white powder (32 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.60 (s, 2H), 7.52 (m, 2H), 7.30 (dd, J=8.8, 8.3 Hz, 2H), 5.49 (s, 2H), 3.90 (m, 2H), 2.82 (t, J=5.1 Hz, 2H), 2.22 (s, 3H), 1.95 (m, 2H); MS: (ES) m/z calculated for C21H20ClFN7O [M+H]+ 440.1, found 440.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH—H2O in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:48])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C#N)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 60 mg (0.16 mmol) of the compound from Example 280 in analogy to the synthesis of the compound from Example 296. 61 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([CH3:4])[CH3:3].[C:13]1([CH2:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>O>[CH3:3][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([NH:1][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4]
Reactant: CC(C)(N)C(O)c1ccccc1
Reactant: O=CCc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(NCCc1ccccc1)C(O)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 6.6 g. (0.03 mole) of α-(1-amino-1-methylethyl)benzenemethanol and 4.8 g. (0.03 mole) of phenylacetaldehyde in 75 ml. benzene is refluxed for 1 hour while 0.7 ml. of water separates in a Dean-Stark trap. The infrared absorption spectrum showed absence of the C=O function and the presence of a C=N function at 1650 cm-1. The solvent is removed in vacuo. The residue of the imino derivative was taken up with 60 ml. of methanol and 1.6 g. of KBH4 is added with stirring at 20°-25° C. After 20 hours, the solution is evaporated in vacuo. The residue is taken up with cold water, and the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration. Recrystallization from methanol gives pure α-{1-methyl-1-[(2-phenylethyl)amino]-ethyl}benzenemethanol as white crystals, m.p. 105°-106° C.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[NH2:14])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[C:13]([NH:14][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:10])([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 41.5 %

Procedure:
Crotonyl chloride (4.7 g, 45 mmol) in 10 ml of methylene chloride was added slowly to a stirred solution of 10 g (45 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline in 50 ml of methylene chloride at 0° C. Ten minutes later 3.6 g (45 mmol) of pyridine was added and, after three hours, the mixture was filtered. The filtered soid was washed with water and triturated in ether to yield 5.4 g of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-butenamide having a melting point of 215°-218° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis-(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. m.p. 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-])=O.Cl>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9]
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ncnc(Cl)c1N
Temperature: 85 °C
Yield: 37.1 %

Procedure:
Iron dust (1000 g, 17.9 mol) was added to a solution of the crude 6-chloro-5-nitropyrimidin-4-amine (500 g, 2.87 mol) in ethanol (5000 mL) and water (1000 mL). A catalytic amount of concentrated hydrochloric acid (10 mL) was slowly added to the reaction mixture over a period of 20 minutes. During the course of the addition the reaction temperature was observed to increase to 85° C. without external heating and the reaction mixture's color changed from yellow-brown to dark red. After the reaction mixture had cooled down to a temperature of 50° C., the slurry was filtered through a Celite pad, which was then washed with ethanol (3×250 mL). The resulting filtrate was concentrated under reduced pressure to give a yellow solid. This solid was then washed with hexane and dried under reduced pressure to give the title compound as a brown solid. (253 g, overall yield over two steps: 37.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1H), 6.71 (broad s, 2H), 4.94 (broad s, 2H). MS (EI) for C4H5ClN4: 145 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cs1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol)[from Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([N:4]([CH2:24][CH3:25])[C:5]1[CH:23]=[CH:22][C:8]([C:9](=[O:21])[CH2:10][N+:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].BrCC(C1C=C[C:33]([N:36](CC)CC)=[CH:32][CH:31]=1)=O>>[C:33]([C:32]1[CH:31]=[C:10]([C:9](=[O:21])[C:8]2[CH:7]=[CH:6][C:5]([N:4]([CH2:2][CH3:3])[CH2:24][CH3:25])=[CH:23][CH:22]=2)[N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=12)#[N:36]
Reactant: CCN(CC)c1ccc(C(=O)C[n+]2cccc3ccccc32)cc1
Reactant: CCN(CC)c1ccc(C(=O)CBr)cc1
Agent: [Br-]
Product: CCN(CC)c1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
1-(4-Diethylamino-phenacyl)-quinolinium bromide: The title compound was prepared from 2-bromo-1-(4-diethylamino phenyl) ethanone (2.23 g, 13.6 mmol), by a method similar to that described for the preparation of Example 1a, and yielded 1.67 g (92%). 1H NMR (DMSO-d6): 9.60 (d, J=6.0 Hz, 1H), 9.52 (d, J=8.4 Hz, 1H), 8.64 (d, J=8.1 Hz, 1H), 8.41 (d, J=9.9 Hz, 1H), 8.39 (d, J=7.5 Hz, 1H), 8.31 (t, J=6.9 Hz, 1H), 8.14 (dd, J=7.8, 6.9 Hz, 1H), 8.04, (d, J=8.7 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.93 (s, 2H), 3.60 (q, J=8.4 Hz, 4H), 1.26 (t, J=6.6 Hz, 6H).