Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35](O)=[O:36]>>[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35]([N:24]([CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][C:3]([OH:28])=[C:2]([Cl:1])[CH:7]=3)[N:16]=2)[CH:18]=1)[CH:25]([CH3:26])[CH3:27])=[O:36]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1cncc(Br)c1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 5-bromo-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 581. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.3 (s, 1H), 8.9 (s, 1H) 8.6 (s, 1H) 8.4 (s, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.8 (s, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][O:26][C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:11]=[C:4]3[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccccn3)nn12
Reactant: Cc1cccc(CO)n1
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cc(N)n3nc(-c4ccccn4)nc3c2)n1

Procedure:
A mixture of 1 eq. 7-bromo-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. (6-methyl-pyridin-2-yl)-methanol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 332 M+H+ (100%).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5](Cl)[N:4]=1)#[N:2].[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:20])=[C:5]([P:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:20])[N:4]=1)#[N:2]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: Clc1ccccc1Cl
Product: N#Cc1nc(P(=O)(c2ccccc2)c2ccccc2)c(P(=O)(c2ccccc2)c2ccccc2)nc1C#N
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a stirred, refluxing solution of 5.00 g of 2,3-dicyano-5,6-dichloropyrazine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 10.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 4 hours and then allowed to stand overnight. The resulting solid was separated by filtration, washed with benzene and twice with hexane, recrystallized from 200 ml of o-dichlorobenzene, and dried at 80° C./0.1 mm (13 Pa) to give 8.08 g of 2,3-dicyano-5,6-bis(diphenylphosphinyl)pyrazine (shown by formula in Claim 5) as a white solid, decomposition beginning at 210° C. Anal. calcd for C30H20N4O2P2 : C, 67.93; H, 3.80; N, 10.56; P, 11.68. Found: C, 67.77; H, 3.92; N, 10.48; P, 11.18.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])=[CH2:2].[CH2:15]1[O:18][CH:16]1[CH3:17].[Cl-].[Li+]>CN(C)C=O>[OH:18][CH:16]([CH3:17])[CH2:15][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[C:7]1=[O:14]
Reactant: CC1CO1
Reactant: C=COCCN1C(=O)NC(C)(C)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)N(CC(C)O)C(C)(C)C1=O

Procedure:
297 g (1.5 mols) of 3-(2-vinyloxyethyl)-5,5-dimethylhydantoin, prepared as described in Example 1, 87 g (1.5 mols) of propylene oxide, 7.5 g of lithium chloride and 750 ml of dimethylformamide are allowed to react for 4 hours and 30 minutes at 90°-112° C. A further 83.5 g (1.44 mols) of propylene oxide are then added dropwise in the course of 3 hours and 30 minutes at 112°-113° C. and the mixture is left to react for a further 15 minutes. It is then concentrated on a rotary evaporator at 80° C. under vacuum from a waterpump and dried to constant weight at 80° C. and 13.3 Pa. 382 g (99.6% of theory) of a brown, clear, viscous crude product are obtained and are purified by distillation. 347.7 g (90.4 g) of a clear, colourless distillate boiling at 149°-152° C./13.3 Pa are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH3:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[O:13]1[CH2:37][CH:14]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[O:36][CH2:35]3)=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1>CO>[OH:13][CH:14]([CH2:37][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:12])[N:5]([CH3:10])[C:6]([CH3:9])([CH3:8])[CH2:7]1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:36])[CH2:35][NH:1][CH:2]3[CH2:3][C:4]([CH3:12])([CH3:11])[N:5]([CH3:10])[C:6]([CH3:8])([CH3:9])[CH2:7]3)=[CH:28][CH:27]=2)([CH3:24])[CH3:25])=[CH:19][CH:18]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: CO
Product: CN1C(C)(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)N(C)C(C)(C)C4)cc3)cc2)CC1(C)C

Procedure:
To 100 ml of methanol were added 12 g of 4-amino-1,2,2,6,6-pentamethylpiperidine and 11 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a similar manner to that described in Example 1, giving the desired compound in the form of white crystals melting at 141°-143° C. The compound had an Rf value of 0.64 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1.I[CH3:12]>C1COCC1>[CH3:12][O:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1
Reactant: COC(=O)C1(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(OC)CC1
Reaction time: 0.25 h

Procedure:
NaH (738 mg, 18.44 mmol; 60% dispersion in oil) was added to a solution of methyl 1-hydroxycyclopropanecarboxylate (1.83 g, 14.18 mmol) in anhydrous THF (15 mL) cooled on an ice bath. The mixture was stirred for 15 minutes then iodomethane (3.22 g, 1.42 mL, 22.69 mmol) was added slowly, and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was quenched with ammonium chloride and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure to give methyl 1-methoxycyclopropanecarboxylate. An aqueous 6N NaOH solution (4 mL) was added to a solution of methyl 1-methoxycyclopropanecarboxylate (1.08 g, 8.3 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 18 hours, then acidified with aqueous 6N HCl and extracted with EtOAc (3×15 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give 1-methoxycyclopropanecarboxylic acid (892 mg, 54% yield) as an oil. 1H NMR (400 MHz, (CD3)2SO) δ 12.40 (br s, 1H), 3.30 (s, 3H), 1.15-1.10 (m, 2H), 1.08-1.04 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[C:3]1=[O:15]>CO.Cl.CCOCC>[CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC1(C)CCCNC1=O

Procedure:
The title compound of Step (B) (440 mg, 1.94 mmol) in 4 ml MeOH and 15 ml 1N HCl in Et2O was stirred at room temperature overnight. The solvent was evaporated and dried in vacuo to provide the title compound of this step as a light yellow solid which was relatively pure and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].C(O)(=O)C.[N:17]([O-])=O.[Na+]>O>[F:1][C:2]([F:11])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:6][N:17]=1
Reactant: Nc1ccccc1CC(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1n[nH]c2ccccc12
Temperature: 25 °C

Procedure:
18.9 parts of 2-(2,2,2-trifluoro-ethyl)-aniline are dissoved in 700 parts by volume of glacial acetic acid. 14 parts by volume of a 50% aqueous solution of sodium nitrite are poured at one go into this well stirred solution. The temperature of the mass rises from 20° C. 27° C. The stirring is maintained at ambient temperature for about 15 hours, after which the intermediate diazo derivative has totally disappeared. A large part of the acetic acid is eliminated by distillation in vacuum so as to give a volume of about 100 parts. Then the solution is run into 160 parts of cold water with stirring. The precipitate of 3-trifluoromethyl-indazole formed is filtered off and washed with water: crude M.p. 98° C. It is recrystallised from boiling water for analysis. White needles of M.p. 104° C. (Kofler stage) are obtained; dry weight after recrystallisation 11.4 parts.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10]2/[CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:13][CH2:14]/2)=[N:7][CH:8]=1.[OH-].[Na+].[H][H]>CO.[Pd]>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCC/C1=C\c1ccc(C(F)(F)F)cn1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCC1Cc1ccc(C(F)(F)F)cn1

Procedure:
To a solution of tert-butyl N-[(2E)-2-{[5-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentyl]carbamate (1.5 g, 4.38 mmol) in methanol (5 ml) was added palladium on carbon (10% wt, 50% wet, 300 mg) and 2M NaOH (5 ml). The resulting reaction was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound. The resulting residue was purified by column chromatography (silica, 0-70% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].[O:25]1CCN(CCOC2C=CC(C(N)CCC)=CC=2)CC1>>[C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:23][CH2:24][O:25][CH2:22][CH2:21]2)=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(N)c1ccc(OCCN2CCOCC2)cc1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 29 except that 1-(4-(2-morpholinoethoxy)phenyl)butan-1-amine (28) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25). This produced a crude product which was purified by flash silica gel column chromatography, eluting with 4:96 mixture of methanol/dichloromethane, to give 32 (370 mg, 76%) as a clear oil: MS (ES+) m/z 346.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>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.[Cu]I>[NH2:16][C:12]1[N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[C:3]([F:18])=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1nccc(-n2cnc3cc(F)c(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1cc2c(cc1F)ncn2-c1ccnc(N)n1)c1nccs1
Temperature: 75 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a pressure tube was added 4-(6-Bromo-5-fluoro-benzoimidazol-1-yl)-pyrimidin-2-ylamine (66%, 250 mg, 0.54 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I) iodide (10.2 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (164.09 mg, 1.07 mmol), degassed with N2 for 5 min and stirred at 75° C. for 3 hr before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (98:2 to 90:10). The product obtained was triturated with methanol to obtain the title compound as an off-white solid (35 mg, 17.1% yield). 1H NMR (500 MHz, DMSO) delta 1.94 (3H, s), 7.08 (1H, s), 7.13 (1H, d, J=5.36 Hz), 7.18 (2H, br. s.), 7.65-7.73 (2H, m), 7.78 (1H, d, J=3.15 Hz), 8.39 (1H, br. s.), 8.64 (1 H, d, J=6.46 Hz), 9.17 (1H, s); LC-MS: m/z+381.40 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]1([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:19]=[C:18]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)[N:17]=2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>O1CCOCC1>[CH:6]1([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:19]=[C:18]([C:29]3[CH:30]=[CH:31][C:32]([NH:33][C:37](=[O:38])[O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:35]=3)[N:17]=2)(=[O:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Yield: 90.6 %

Procedure:
Sodium bicarbonate (113 mg, 1.35 mmol) was added to a solution of 4-[4-(cyclohexylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (370 mg, 0.86 mmol) in 1,4-dioxane (5 mL). Phenyl chloroformate (0.124 mL, 0.99 mmol) was added dropwise and the resultant mixture was stirred at RT for 5 hours. The resulting mixture was evaporated to dryness and the residue partitioned between DCM (5 mL) and water (5 mL). The organic layer was separated and evaporated to dryness. The crude residue was triturated with diethyl ether to give the desired material (429 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([O:18][CH3:19])=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>[Pd].CCOC(C)=O.CO>[NH2:15][C:8]1[CH:7]=[C:6]([O:18][CH3:19])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OCCCl)c(OC)cc1N
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.07 g, 14.1 mmol) under argon was added 10% palladium on carbon and in EtOAc (150 mL) and MeOH (50 mL). The flask was flushed with H2 (g) and stirred under H2 (1 atm) for 30 minutes. The mixture was filtered through Celite and concentrated in vacuo to give methyl 2-amino-5-(2-chloroethoxy)-4-methoxybenzoate (3.61 g, 13.9 mmol, 99%). 1H NMR (300 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.52 (br s, 2H), 6.38 (s, 1H), 4.07 (t, 2H), 3.85 (t, 2H), 3.77 (s, 3H), 3.75 (s, 3H); LC-MS (ESI) m/z 260 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.N>CO.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1
Reaction time: 1 h

Procedure:
4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol) (Lancaster Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70%-yield, mp 132-133° C.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NS(C)(=O)=O
Reaction time: 16 h

Procedure:
To 4.54 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylaniline in 25 ml pyridine, add 1.94 g (17 mmole) methanesulfonyl chloride. After 16 hours, pour onto 200 ml H2O and filter the solid. Recrystallize from Et2O-hexane to obtain the product; m.p. 109°-110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[C:27]([O:32][CH3:33])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][C:27]=1[O:32][CH3:33])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(Br)ccc1I
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: COc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-bromo-1-iodo-2-methoxy-benzene in analogy to Example 1a): MS (ISP): 490.0 (M+H)+ and 390.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([N:6]([C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: Cc1cnc(NC(=O)C(C)C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)C(C)C)c1ncc(C)o1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-isobutyramido-5-methyloxazole (2.10 g., 0.0124 mol), prepared as above, was dissolved in dry dimethylformamide (10 mls.) and cooled to below 5° C. To this was added sodium hydride (0.70 g., 0.0145 mol.) portionwise, keeping the temperature below 5° C. After the addition, the mixture was stirred for a further 30 minutes at 5° C and then allowed to warm to room temperature. The iodobutane (5.0 g., 0.0271 mol.) was added. The mixture was stirred overnight, the solvent was evaporated under reduced pressure and the residue was partitioned between water (50 mls.) and ether (50 mls.). The organic phase was then washed with 2N HCl (2 × 25 mls.), water (1 × 25 mls.), 10% aqueous sodium carbonate (3 × 25 mls.) and water (3 × 25 mls.). The organic phase was then dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled from a Kugelrohr, air bath temperature 100° C/0.1 mm. Yield = 1.74 g. (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11]O)[NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2ccc(Cl)cc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65° C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32%). The aqueous layer was extracted with tert-butyl methyl ether (3×200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1O
Product: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
The stirred mixture of 48.5 g of 2-amino-3-cyano-4-hydroxy-6-nitroquinoline and 550 mL of phosphoryl chloride was refluxed for 4 hours. The reaction mixture was concentrated to half of its volume and the residue was poured onto 1500 g of ice. The yellow precipitate was filtered off, washed with water to give 60.5 g of solid. 25 g of this solid was stirred at room temperature in 500 mL of 0.5 N HCl for 6 hours, then the precipitate was filtered off, washed with water to give 18.5 g of product, m.p.: >360° C. LC-MS: MH+ 249; Ret. time: 5.94 min.