Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[O:12][C:8]3=2)[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29](Cl)[CH:28]=[CH:27]2.C(=O)(O)[O-].[Na+]>>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C@@H:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:18][CH2:19]1)[CH:28]=[CH:27]2
Reactant: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Reactant: Clc1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4cc(Br)ccc4n2)CC1)O3
Temperature: 95 °C

Procedure:
A mixture of 8-methyl-2-piperazin-1-ylmethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline of Step B′ (0.493 g, 1.64 mmol) and 6-bromo-2-chloroquinoline of Example 1, Step A (0.507 g) is heated at 95° C. under nitrogen for 6 hours, followed by heating at 105° C. for 4 hours. The mixture is cooled, poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica Merck-60 using a gradient of methanol (0.5–2%) in dichloromethane-hexane (45:55), to provide the title compound (0.147 g) identical to the compound of Example 27, Step C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methoxy-4-methylbenzonitrile (0.438 g, 2.98 mmol) in CCl4 (6 mL) was added recrystallized N-bromosuccinimide (0.544 g, 3.05 mmol) followed by benzoyl peroxide (47 mg, 0.19 mmol). The resultant mixture was heated to reflux for 45 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (30 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.46 g (68%) of 4-(bromomethyl)-2-methoxybenzonitrile as a white solid. 1H NMR (CDCl3) δ3.96 (s, 3H), 4.45 (s, 2H), 6.99 (s, 1H), 7.03 (d, 1H, J=9 Hz), 7.53 (d, 1H, J=9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O1CCOCC1>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:13])[CH3:12]
Reactant: Nc1ccccc1B(O)O
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccccc1B(O)O
Temperature: 100 °C
Yield: 83.4 %

Procedure:
To a solution of o-aminophenylboronic acid (6.73 g, 49.1 mmoles) in dioxane (100 ml) is added acetic anhydride (25.1 g, 246 mmoles). The reaction is heated at 100° C. for 17 hours. After cooling, the reaction volatiles are removed under reduced pressure to leave a thick yellow gel, which after chromatography affords o-N-acetylaminophenylboronic acid (7.33 g).
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20].N1CCCCC1.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#C>CO.[Cu]I>[NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:41]#[C:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20]
Reactant: C#CCCCCCOC
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: C1CCNCC1
Product: COCCCCC#Cc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A round bottomed flask was charged with copper (1) iodide (0.102 g, 0.536 mmol), bis(tripheynlphosphine)palladium(II)dichloride (1.128 g, 1.608 mmol), and (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (20 g, 53.6 mmol) (that had been free based by partitioning between EtOAc and saturated NaHCO3. The organic layer was separated, dried (NaSO4), filtered and concentrated) THF (150 mL) was added and the reaction mixture was purged with nitrogen. After 5 min piperidine (23.88 mL, 241 mmol) and 7-methoxyhept-1-yne (6.0 g, 54 mmol) was added. The reaction mixture was heated to about 65° C. After about 8 hours additional 7-methoxyhept-1-yne (3.1 g, 27 mmol) was added. After about 20 hours total the reaction mixture was cooled to about room temperature and partitioned between EtOAc/NaHCO3. The organic layer was separated dried (Na2SO4) filtered and concentrated. The crude mixture was purified by chromatography on silica gel (eluting with EtOAc/MeOH). The fractions containing the desired product were concentrated in vacuo. The dark brown oil was dissolved in MeOH (50 mL) and a solution of (2R,3R)-2,3-dihydroxysuccinic acid (9.65 g, 64.3 mmol) in MeOH (15 mL) was added. The solution was concentrated in vacuo and the resulting solid was slurried in isopropyl alcohol (approx 100 mL), filtered and dried in vacuo to provide (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhex-1-ynyl)phenyl)cyclopentanecarboxylate, L-tartaric acid (25 g, 52.1 mmol, 97% yield) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde (7.24 gm, 58.4 mmol) and concentrated H2SO4 (10 ml) in glacial HOAc (116 ml) was stirred at room temperature for 2 days. The solution was poured into H2O (250 ml) and neutralized with 10% NaOH (200 ml). The aqueous layer was extracted once with Et2O and the Et2O layer was washed successively with H2O, saturated NaHCO3 (twice) and brine, then dried (magnesium sulfate). Filtration and removal of the solvent afforded a yellow solid, which was recrystallized from hot hexane to give the title compound (7.94 gm, 60%) as light yellow needles.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.[C:17](Cl)(=O)[CH2:18][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][CH2:32][CH2:33][CH3:34]>ClCCl.N1C=CC=CC=1>[CH2:17]([O:1][CH:2]([CH2:15][O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)[CH2:18][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][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCC(O)C#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(C#Cc1ccc(-c2cccs2)s1)OCCCCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
170 mg (0.68 mmole) of 5-(3,4-dihydroxy-1-butynyl)2,2-bithiophene was dissolved in a mixture of 10 ml of dichloromethane and 0.2 ml of pyridine. 0.7 g of stearoyl chloride dissolved in 10 ml of dichloromethane was then dropped into the reaction mixture in ice bath. This reaction solution was stirred for 2 days. It was monitored by thin layer chromatography to determine if there were 3 products obtained, i.e. a mixture of 1 diester and 2 monoesters.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=S)[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1.[Na+].[Na+].[N:44]#[C:45][NH-:46].N#C[NH-]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=[N:46][C:45]#[N:44])[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1
Reactant: N#C[NH-]
Reactant: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(NC(=NC#N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
As illustrated in the scheme above, a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[4-(4-morpholinyl)-1-naphthalenyl]-thiourea (EXAMPLE 11, made according to General Procedure 3) (0.058 g, 0.1 mmol) and silver triflate (0.077 g, 0.3 mmol) in dichloromethane (2 ml) was combined with cyanamide disodium salt (1 mmol) and stirred at room temperature for 3 h. The reaction mixture was then diluted with dichloromethane (10 ml) and washed with brine (2×5 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was washed with ether (2×10 ml) and the polar isomer of the title compound (0.023 g, 380%) was obtained as pale yellow solid. The ether layer was concentrated in vacuo and purified by column chromatography (1:1 EtOAc:CH2Cl2) to give the non-polar isomer of the title compound (0.009 g, 15%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.Cl.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:20]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1cnc(C2CCNC2)cn1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3cnccn3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (15.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.0 mg). Calcd for C19H18N4O2: 334.1430, found 334.1426.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.12 mmol) in DCM (2 mL) at 0° C. was added methyl 4-chloro-4-oxo-butanoate (19 mg, 15 μL, 0.12 mmol) followed by the addition of triethylamine (50 mg, 69 μL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude material was dissolved in DMSO and purified by reverse phase HPLC using 1-99% MeOH in H2O to obtain methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate, which was re-dissolved in THF (1.0 mL), treated with NaOH (996 μL of 2.5 M, 2.5 mmol) and stirred for 18 h at room temperature. The reaction mixture was then acidified with conc. HCl till pH7 and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified via reverse phase HPLC using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoic acid (5 mg, 11%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.66 (d, J=4.1 Hz, 2H), 7.27 (dd, J=6.0, 3.1 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 4.34 (s, 1H), 4.27 (s, 1H), 3.84 (t, J=5.6 Hz, 2H), 2.85 (s, 1H), 2.80-2.65 (m, 3H), 2.56-2.47 (m, 2H). LC/MS m/z 393.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: Cc1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (170 mg), (4-methylphenyl)methanol (148 mg) and tributylphosphine (454 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (458 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[O:12])#[N:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][SH:18])[CH3:14].C(N(CC)CC)C>C(OCC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([S:18][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=[O:12])#[N:2]
Reactant: N#CCCCCCCC=CC=O
Reactant: CCOC(CS)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(CSC(=CC=O)CCCCCCC#N)OCC
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 1.8 g of 9-cyano-2-nonenal, 1.4 g of 2,2-diethoxy-ethane-thiol and 50 μl of triethylamine is allowed to stand at room temperature for 48 hours. It is taken up in 100 ml of diethyl ether, the solution washed with water, dried and evaporated, to yield the 9-cyano-3-(2,2-diethoxy-ethylmercapto)-nonenal, showing in NMR spectrum peaks at 9.78, 4.55, 3.57 and 2.61 ppm.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:12][C:11]1([CH2:10][CH2:9][C:7]2[S:8][C:4]([C:1]([CH3:2])=[O:3])=[CH:5][CH:6]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCCO
Reactant: CC(=O)CCc1ccc(C(C)=O)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: CC(=O)c1ccc(CCC2(C)OCCO2)s1

Procedure:
4-(5-Acetyl-2-thienyl)-2-butanone (Tetrahedron 35, 1979, 329) was reacted with ethylene glycol, triethyl orthoformate and p-toluenesulphonic acid in methylene chloride to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophene carboxylic acid. With sodium borohydride there was obtained therefrom 5-(3-hydroxybutyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium carbonate into the methyl ester. Treatment with p-toluenesulphochloride in pyridine and reaction with sodium azide in dimethyl sulphoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which there was obtained by saponification the corresponding acid. The acid was treated with thionyl chloride to give the acid chloride from which there was obtained with concentrated ammonia in ether 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (R,S)-5-(3-aminobutyl)-2-thiophenecarboxamide of melting point 65°-75°. UV: ε256 =7780; ε275 =9900.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([N:10]([C:16]([CH3:23])([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:17])[C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].ClC1C=CC=C(Cl)C=1C(N1C2C=CN=CC=2C=C1)=O>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27]([N:1]1[C:9]2[CH:8]=[C:7]([N:10]([C:16]([CH3:23])([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:17])[C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:28]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2[nH]ccc2cn1
Agent: O=C(c1c(Cl)cccc1Cl)n1ccc2cnccc21
Product: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2c(ccn2C(=O)c2c(Cl)cccc2Cl)cn1

Procedure:
The compound was prepared from N-(1H-pyrrolo[3,2-c]pyridin-6-yl)-N-(2,4,4-trimethylpentan-2-yl)cyclopropanecarboxamide and 2,6-dichlorobenzoyl chloride following the procedure same as that of (2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone
Reaction SMILES: O=[O+][O-].[O:4]=O.[Cl:6][C:7]1[C:8]([CH:22]=C)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:8]([CH:22]=[O:4])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2
Reactant: C=Cc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: O=O
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of ozone and oxygen was bubbled gently through a stirred solution of 6,7-dichloro-2,3-dimethoxy-5-ethenylquinoxaline (1.76 g, 6.2 mmol) in chloroform (200 mL) at -60° C. until a blue colour persisted. The solution was purged with nitrogen, and then triphenylphosphine (3.23 g, 12.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 16 hours. The chloroform was removed under reduced pressure and the residue purified by flash chromatography (eluting with toluene) to give 6,7-dichloro-2,3-dimethoxy-5-formylquinoxaline (1.60 g, 90%) as a fluffy white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[N:10]([C:24](=[O:25])[NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]2=[O:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)NC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 50 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then cyclohexylisocyanate (626 mg., 5 mmoles) were added. The reaction mixture was stirred for 19 hours at room temperature, washed in sequence with two portions of 1 N sodium hydroxide, two portions of 1 N hydrochloric acid and once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. Recrystallization from toluene gave purified 5-(5-chloro-2-methoxyphenyl)-3-cyclohexylcarbamoyloxazolidine-2,4-dione [435 mg., m.p. 150°-153° C., ir (KBr) 1818, 1761, 1527, 1493, 1364 cm-1 ].
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1.CO.[OH-].[K+]>O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:20])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 94 %

Procedure:
To a 1L round-bottom flask were added 3-[4-(6-Hydroxy-hexyloxy)-phenyl]-acrylic acid methyl ester (27.82 g, 100 mmol) and MeOH (250 mL) and H2O (80 mL) to render a yellow solution. KOH pellets (8.42 g, 150 mmol) was added in portions. The resulting solution was placed in an oil bath at 50° C. under N2 after the flask was equipped with a water condenser. After 24 h, HPLC analysis indicated more than 95% conversion. The solution was concentrated by rotary evaporation to remove most organic solvent. The remaining solution was diluted with ice cold H2O (400 mL) and cooled in an ice bath. Upon vigorous stirring, concentrated HCl solution (ca. 12 mL) was added dropwise to result in a white slurry (pH 3). The slurry was filtered with a Büchner funnel and the solid was rinsed with additional H2O (ca. 500 mL) and then transferred to a recrystallization dish. After drying overnight in the air, the solid was transferred to an amber bottle, cooled in a dry ice box for 1 h and then lyophilized for 16 h. The hydroxy acid weighed 24.9 g (94% yield).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:16]=1[O:23][CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32].[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]#[C:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:39]([O:38][C:33]([C:34]1[C:35]([CH3:36])=[N:14][N:15]2[C:16]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][C:20]=12)=[O:37])[CH3:40]
Reactant: CC#CC(=O)OCC
Reactant: CCc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A solution of 1.88 g (1.54 mmol, 38% purity) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-ethylpyridinium 2,4,6-trimethylbenzenesulphonate (Example 166A) in 12 ml of N,N-Dimethylformamide was admixed with 0.35 g (3.08 mmol) of ethyl 2-butynoate (CAS: 4341-76-8) and 0.64 g (4.61 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated and the residue was partitioned between water and ethyl acetate. The organic phase was removed, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane/ethyl acetate, gradient 0% to 10%), which gave 0.29 g (35% yield, 70% purity) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18](F)(F)F)[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>>[CH2:26]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 19.4 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.027 g) as a white solid. Used as is without further characterization.