Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[ClH:20].[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[ClH:1].[ClH:20].[CH:21]1([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:3]=3)[CH2:26][CH2:25]2)[CH2:23][CH2:22]1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc3ccccc3c(N3CCN(C4CC4)CC3)n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
1-Chloro-3-(4-methoxyphenyl)isoquinoline (514 mg), and 1-cyclopropylpiperazine hydrochloride salt (378 mg) described in JP-A 62-129273 were dissolved in dimethyl sulfoxide (7 ml), followed by the addition of potassium carbonate (788 mg), and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system). The resulting product was converted into a hydrochloride in a conventional manner, and then recrystallized from ethanol/isopropyl ether, to give the hydrochloride of the title compound as yellow crystals (136 mg, yield; 16%).
Reaction SMILES: C(O)=O.C(N(CC)CC)C.CC1(C)[O:19][C:17](=[O:18])[CH2:16][C:14](=O)O1.C(=O)[C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1>C(#N)C>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:14][CH2:16][C:17]([OH:19])=[O:18])[CH:31]=[CH:30][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC#N
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 82 °C
Yield: 68.5 %

Procedure:
After adding 2.1 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 to 20 ml of acetonitrile, 3.60 g (0.025 mol) of Meldrum's acid and 4.15 g (0.025 mol) of veratraldehyde were added to the reaction mixture. After heating same to its boiling point (82° C.) within 30 minutes and refluxing it for 4 hours, the acetonitrile was evaporated under reduced pressure, then the method of Example 1 was followed to give 3.6 g of a product, m.p.: 91°-93.5° C., which was recrystallized from aqueous methanol of 50% by volume.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2ccccc2O)cc1
Yield: 92.9 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 2′-hydroxybiphenyl-4-carboxylate (498 mg) and aqueous sodium hydroxide (1N, 4.81 ml) and the reaction mixture was treated to afford the title compound (434 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].[C:20](O)(=O)C.C(N)=N.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][CH:20]=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: N=CN
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidin-6-one (0.3 g), formamidine acetate (0.18 g) and anhydrous sodium acetate (0.1 g) was heated in an oil bath at 155°-165° C. for 2½ hours. The mixture melted and then resolidified. Ethanol (1 ml) was added and the title compound was collected by filtration, 0.31 g, m.p. 256°-258° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH:13]1C(=O)OC(C)(C)[O:15][C:14]1=[O:22])[CH2:11][CH3:12].CN(C=O)C.O>CCOCC>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH2:11][CH3:12])[CH2:13][C:14]([OH:22])=[O:15]
Reactant: CCC(c1cccc(OC)c1F)C1C(=O)OC(C)(C)OC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCC(CC(=O)O)c1cccc(OC)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A 500 mL round bottom flask was charged with 5-(1-(2-fluoro-3-methoxyphenyl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.C (5.17 g, 16.7 mmol) and 10:1 DMF/water (80 mL). The pale yellow solution was stirred overnight at 90° C., cooled to room temperature, and diluted with ether. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated to afford 3-(2-fluoro-3-methoxyphenyl)pentanoic acid 77.D (3.44 g, 91.3% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[C:2]1[CH:8]=O.COP([CH:16]([NH:20]C(=O)C)[C:17](=[O:19])[CH3:18])(=O)OC.N12CCCN=C1CCCCC2>>[S:1]1[C:2]2=[CH:8][N:20]=[C:16]([C:17](=[O:19])[CH3:18])[CH:6]=[C:3]2[CH:4]=[CH:5]1
Reactant: COP(=O)(OC)C(NC(C)=O)C(C)=O
Reactant: O=Cc1ccsc1C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)c1cc2ccsc2cn1

Procedure:
Compounds of Formula I in which ring A is a thieno[2,3-c]pyridinyl can be prepared from a 2,3-thiophenedicarboxaldehyde (XLVI) (see Scheme X). The pyridinyl ring is formed by cooling a solution of the 2,3-thiophenedicarboxaldehyde (XLVI) in an organic solvent to about −10° C. to about 10° C., then adding about 1 eq. to about 1.5 eq. of (1-acetylamino-2-oxo-propyl)-phosphonic acid dimethyl ester (XLVII) and about 1 eq. to about 1.5 eq of a hindered aprotic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The solution is allowed to come to room temperature and is stirred for about 8 h to about 20 h to form 1-thieno[2,3-c]pyridin-5-yl-ethanone (XLVIII).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:63])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:64](OS(C(F)(F)F)(=O)=O)([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65].N1C(C)=CC=CC=1C>CCOC(C)=O.CCCCCC>[Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:60])([CH3:59])[CH3:61])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@H](O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: Cc1cccc(C)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 95529.9 %

Procedure:
The procedure for 35 was used with alcohol 66 (1.70 g, 1.85 μmol), TBSOTf (0.94 mL, 4.07 mmol) and 2,6-lutidine (0.51 mL, 4.44 mmol) to yield 67 (1.82 g, 96%) by flash column chromatography (EtOAc/hexane 1:19) as a colorless oil: IR (CHCl3) 2956, 2856, 1471, 1448, 1254, 1092, 1004, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.77-7.75 (m, 6H), 7.57-7.47 (m, 9H), 6.02-5.87 (m, 2H), 5.76 (t, J=10.8 Hz, 1H), 5.61 (dd, J=10.8, 8.5 Hz, 1H), 4.88 (m, 1H), 4.24 (m, 1H), 3.88 (m, 4H), 3.75 (m, 1H), 2.94 (m, 1H), 2.73 (m, 1H), 1.83 (m, 2H), 1.75 (m, 2H), 1.57 (m, 1H), 1.46-1.41 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.30(d, J=6.3 Hz, 3H), 1.24-1.13 (m, 39H), 0.44-0.34 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 144.4, 134.4, 132.9, 132.2, 128.7, 127.7, 126.8, 86.8, 80.2, 72.3, 66.6, 65.1, 63.6, 42.4, 41.6, 38.4, 35.7, 31.6, 29.9, 26.3, 26.0, 19.6, 18.5, 18.4, 18.2, 15.1, 13.2, −2.9, −3.6, −3.7, −4.2, −5.2; LRMS (ESI) 1051.6 [M+Na]+, 918.6, 769.5, 637.4, 413.2; HRMS (ESI) calcd for C61H104O5Si4Na 1051.6859 [M+Na]+, found 1051.6848 [α]20D−8.3 (c 2.4, CHCl3).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH3:25].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:24]([O:26][C:27](/[CH:28]=[CH:29]/[C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:23])=[CH:10][CH:9]=1)[CH:12]=[C:13]2[C:21]#[N:22])=[O:30])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(c1)c(C#N)cn2-c1ccc(C(=O)O)cc1
Yield: 35.9 %

Procedure:
A solution of 4-(5-bromo-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.1 g), acrylic acid ethyl ester (0.11 g) and triethylamine (0.082 g) in N,N-dimethylformamide (2 mL) was stirred in the presence of palladium (II) acetate (0.0061 g) and triphenylphosphine (0.014 g) at 100° C. for 30 hours. This reaction mixture was poured into water, and this resulting mixture was extracted with ethyl acetate twice. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.035 g).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O.ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: COCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COCCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.1 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0□ C. was added 2-methoxy-1-ethanesulfonyl chloride (J. Chem. Soc., 1968, 2895; 155 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) was added, and the mixture stirred for 10 minutes. The organic phase was washed further with water (5 ml), separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 60:40:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (3 mg, 1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Palladium-on-carbon (10% w/w; 0.25 g.) was added to a solution of (C) (1.5 g.) in tetrahydrofuran (50 ml.) in a hydrogenation bottle. The mixture was hydrogenated at 3.45 bars for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil was purified by flash chromatography on silica gel (200 ml.) eluting with 1:1 v/v ethyl acetate:hexane, to give methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (1.12 g., 82%) as a viscous oil; NMR: 3.29 (br,2 H,NH2), 3.88 (s,3 H, CO.OCH3), 3.91 (s,3 H, OCH3), 4.03 (s,2 H, CH2.Ar), 6.64 (dd,1 H), 6.78 (m,2 H), 7.10 (m,2 H), 7.44 (m,2 H), 7.68 (br,1 H, H1 -indole).
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:19][C:18]1[C:2]([CH3:1])=[CH:3][C:4]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: Fc1ccccn1
Reactant: Cc1cc2nc(C=Cc3ccccc3)[nH]c2cc1C
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Cc1cc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2cc1C

Procedure:
The titled compound was prepared from 5,6dimethyl-2-styryl-1H-benzimidazole and 2-fluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). MW: 325.42; mp: 135.8-137.0° C.; 1H-NMR (CDCl3) δ: 8.77 (1H, ddd, J=4.8, 1.8, 0.7 Hz), 7.98 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.94 (1H, d, J=16.1 Hz), 7.59 (1H, s) 7.55-7.42 (4H, m), 7.38-7.26 (3H, m), 7.23 (1H, s), 7.12 (1H, d, J=16.1 Hz), 2.39 (3H, s), 2.35 (3H, s).
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]Br)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([NH:13][C:14]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:17]([Br:35])[CH:16]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN2CCOCC2)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 100.3 %

Procedure:
To a solution of N-dodecyl-3-bromo-4-(2-bromoethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.294 g, 0.46 mmol, 1 eq) in CH3CN (4 mL) was added morpholine (0.50 mL, 0.57 mmol 1.24 eq) and K2CO3 (0.509 g, 3.68 mmol, 8 eq). The reaction was heated at reflux overnight. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc:hexane) to afford the title compound (0.296 g, 100%) as a colorless oil. 1H NMR (DMSO-d6) δ 8.53 (bt, 1H); 8.11 (d, 1H); 7.88–7.83 (m, 3H); 7.78 (d, 1H); 7.72 (dd, 1H); 3.63 (dd, 2H); 3.40 (dd, 4H); 3.21 (dd, 2H); 2.38 (dd, 2H); 2.15 (dd, 4H); 1.48 (dd, 2H); 1.22 (m, 18H); 0.82 (t, 3H); IR (KBr) 3400, 2900, 2800, 1630, 1540, 1450, 1330, 1310, 1170, 1120, 700 cm−1; mass spectrum [(+)APCI], m/z 641/643 (M+H)+; Anal. Calcd. for C31H34BrF3N2O4: C, 59.90; H, 6.91; N, 4.37. Found: C, 58.58; H, 7.01; N, 4.18.
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>CCOC(C)=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:21][OH:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(CCC(CO)(CO)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.8 %

Procedure:
A mixture of 3.07 g (10.0 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol and 3.00 g (30.0 mmol) of KHCO3 in 200 mL of EtOAc and 150 mL of H2O was treated with 1.50 mL (10.0 mmol) of benzyl chloroformate, then stirred at rt for 2 h. The organic layer of the reaction mixture was separated, dried over MgSO4 and concentrated to afford 5.29 g of the title compound: 1H NMR (500 Mhz) δ0.88 (t, J=6.5, 3H), 1.22-1.34 (12H), 1.55-1.60 (m, 2H), 1.87-1.91 (m, 2H), 2.53-2.59 (4H), 3.23 (br s, 2H), 3.67 (dd, J=6.5, 11.5, 1H), 3.90 (dd, J=6.5, 11.5, 1H), 5.08 (s, 2H), 5.30 (s, 1H), 7.05-7.09 (4H), 7.32-7.36 (5H); HPLC A 5.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1ccccc1CN=C=O
Product: Cc1ccccc1CNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 70.1 %

Procedure:
Example 6 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-2-methylbenzene (0.0201 g) to give the title compound (0.0269 g). LC-MS (System A): Rt 2.31 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]([C:19]1[CH:23]=[C:22]([NH:24][C:25](=[O:38])[C:26]([CH3:37])([S:28]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH3:27])[O:21][N:20]=1)([CH3:18])[CH3:17]>CC(C)=O.ClCCl>[CH3:17][C:16]([C:19]1[CH:23]=[C:22]([NH:24][C:25](=[O:38])[C:26]([CH3:37])([S:28]([CH:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)(=[O:30])=[O:29])[CH3:27])[O:21][N:20]=1)([CH3:18])[C:15]([OH:3])=[O:14]
Reactant: CC(C)=O
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 64 %

Procedure:
Jones reagent (1.28 mL, 10.24 mmol) is added dropwise to a solution of N-[3-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (560 mg, 1.50 mmol) in a mixture of acetone (4 mL) and dichloromethane (4 mL) at 0° C. The reaction mixture is stirred at 0° C. for 3 minutes then room temperature for 2.5 h. After this time, the reaction mixture is diluted with acetone and filtered through celite and the celite is washed with acetone. The filtrate is concentrated under reduced pressure. The residue is dispersed in water and filtered to yield the title compound. Yield: 64%; m/z 389 [M+H].
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH3:3].[CH2:15]([OH:17])[CH3:16]>C(OCC)C>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:17][CH2:15][CH3:16])=[NH:13])[CH3:3]
Reactant: CCOC(=O)CCCCCCC#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CCCCCCC(=O)OCC
Yield: 117.7 %

Procedure:
Bubble hydrogen chloride gas into a solution of 7-cyanoheptanoic acid ethyl ester (3.7 g, 20.0 mmol) in ethanol (24 mL, 40 mmol) and diethyl ether (100 mL) at 0° C. for 15 minutes. Remove the solvent under reduced pressure to provide 7-ethoxycarbonimidoylheptanoic acid ethyl ester (5.4 g, >99%), which is used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:15])=O.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:3][OH:2])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: COC(=O)c1ccc2ncnc(Cl)c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc2ncnc(Cl)c2c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of methyl-4-chloroquinazoline-6-carboxylate (3.5 g, 0.015 mol) in dry THF (35 mL) at −25° C. was added DIBAL-H (4.4 g, 0.031 mol) and stirred at −25° C. to RT for 2 h. The reaction mixture was cooled to −10° C. and quenched with 10% aqueous NaHCO3 (9 mL). The reaction mixture was extracted with ethylacetate (100 mL), washed with water, brine and dried. The solvent was removed under vacuum to give 4-chloroquinazoline-6-yl methanol (2 g, 66%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH2:18])[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(N(CC)CC)C.O>C1COCC1>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Reactant: CCCN=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NC(=O)NCCC)nc2ccc([N+](=O)[O-])cc12
Yield: 80.5 %

Procedure:
After 200 mg (0.82 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was dissolved in 10 ml of THF, 153 mg (1.80 mmol) of propylisocyanate and 0.13 ml (0.90 mmol) of triethylamine were added thereto, and then the reaction mixture was subjected to heating under reflux overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 218 mg (80.5%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](O)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Br)([Br:31])=O.N1C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12]([Br:31])([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(c1cccnc1)C(F)(F)C3
Reactant: O=S(Br)Br
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Br)(c1cccnc1)C(F)(F)C3
Temperature: 70 °C

Procedure:
Into a 500 ml flask containing the product from step (a) (5.9 g, 15.20 mmol) in DCE (50 ml), thionyl bromide (5.89 ml, 76.03 mmol) was added, followed by pyridine (123 μL, 1.52 mmol). The stirred reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was then allowed to cool to room temperature and was carefully poured over ice-cold saturated aqueous Na2CO3 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a pale red semi-solid that was used without further purification. MS: ESI (positive): 451, 453 (M+1).