Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([NH:8][CH2:9][CH3:10])[CH:7]=1>[Ni].CO.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: CCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 85.7 %

Procedure:
A suspension of (5-bromo-2-nitro-phenyl)-ethyl-amine (Step 26.3) (6 g, 24.48 mmol) and Raney nickel (2 g) in MeOH/THF (1:1 v/v, 600 mL) is stirred for 9 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 95:5→85:15) to afford 4.51 g of the title compound as a black oil: ESI-MS: 213.1/215.1 [M−H]−; tR=2.53 min (System 1); TLC: Rf=0.57 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([C@@H:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Reactant: CC1=CC[C@H](C(=O)Cl)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
(R)-4-methylcyclohex-3-enecarbonyl chloride 504 (2.65 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester 505 (250 mg, 0.66 mmol) and potassium phosphate tribasic (562 mg, 2.65 mmol) were suspended in dichloroethane (1.7 mL), sealed with a cap and heated to 90° C. After 16 hours, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-40% EtOAc:Hexanes) afforded 220 mg (67% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-((1R)-4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester 506 as a beige foam.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CC[C@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@H:44]5[CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-N—Boc 3-amino pyrrolidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.28 (m, 1 H) 1.30-1.47 (m, 2 H) 1.51-1.72 (m, 4 H) 1.73-1.88 (m, 4 H) 1.90-2.06 (m, 1 H) 2.64 (dd, J=11.24, 4.93 Hz, 1 H) 2.75 (ddd, J=10.67, 7.89, 6.44 Hz, 1 H) 2.82-3.03 (m, 2 H) 3.31 (s, 3 H) 3.94 (s, 3 H) 4.06 (t, J=13.52 Hz, 2 H) 4.23-4.37 (m, 1 H) 4.39-4.53 (m, 1 H) 7.44-7.50 (m, 1 H) 7.51 (d, J=1.52 Hz, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.23 (d, J=7.07 Hz, 1 H) 8.26 (d, J=8.34 Hz, 1 H). Melting point: 258-263° C. [M+H] calc'd for C26H33F2N7O3 530; found 530.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CC(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ccnc2c1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Nc2ccnc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a mixture of 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline (42 mg, 0.14 mmol) and 4-(tert-butyl)aniline (41 mg, 0.29 mmol) in 2-propanol (10 mL) at reflux for 3 hours. Evaporate the mixture, add 1M NaOH (10 mL), extract twice with EtOAc (10 mL each), dry (Na2SO4), and evaporate to provide the crude product. Purify by silica gel chromatography, eluting with 75% hexane-EtOAc to provide (4-tert-butyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine as a white solid. Mass spec. 420.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.Cl.[F:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[N+:13]([C:9]1[CH:8]=[C:7]([CH:5]([C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[NH:30][C@H:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH3:29])[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: C[C@H](N)c1cccc(F)c1
Reactant: COc1ccccc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccccc1C(N[C@@H](C)c1cccc(F)c1)c1cccc([N+](=O)[O-])c1
Yield: 104.8 %

Procedure:
In a similar manner to that described in Example (1a), 2-methoxy-3′-nitrobenzophenone (2.0 g), (S)-1-(3-fluorophenyl)ethylamine hydrochloride (2.73 g), triethylamine (6.50 ml), titanium tetrachloride (1.03 ml), sodium cyanoborohydride (2.15 g) and acetic acid (0.67 ml) were reacted, to afford the title compound (3.10 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:12]3[C:11]=2[CH:10]=1.[Br:36]N1C(=O)CCC1=O>CN(C=O)C>[Br:36][C:16]1[C:15]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH:12]3[C:11]=2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)ccc1N2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc(Br)c1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A dry 25 mL round bottom flask was charged with di(tert-butyl) 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (0.38 g, 0.74 mmol), DMF (10 mL), N-bromosuccinimide (0.21 g, 1.11 mmol), and stirred at ambient temperature for 18 hours. The reaction was concentrated under high vacuum to remove DMF and partitioned between water and ethyl acetate (2X). The organics were combined, dried with MgSO4, filtered and concentrated to give 461 mg of a crude orange brown oil. Purification of the crude on a 40 gram silica Biotage column using 10% ethyl acetate in heptane gave 217 mg (50%) of di(tert-butyl) 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate as a pale yellow foam.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)C.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
To 112.0 g (0.38 mol) of methyl 4-dodecylpyrrole-2-carboxylate prepared in Example 35 were added 1.45 liters of ethanol, 1.45 liters of water and 31.0 g (0.74 mol) of 95% sodium hydroxide, and the whole was heated under reflux for 2 hours. At 80° C., 1.45 liters of hot water was added and, at the same temperature, 6N sulfuric acid was added gradually to adjust the reaction solution to pH 2. After cooling the mixture to 45° C., precipitated crystals were filtered and washed with water. The crystals were dissolved in 4 liters of tetrahydrofuran, and the solution was washed twice with 1 liter of a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give crystals, which were then recrystallized from a mixed solvent of 600 ml of tetrahydrofurn and 600 ml of hexane to obtain 92.6 g (87% yield) of 4 -dodecylpyrrole-2-carboxylic acid as white crystals, m.p. 152°-153° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[CH:6][CH:5]=1.COC1C=CC(O)=CC=1.N1C=CC=CC=1.[C:35](Cl)(=[O:39])[C:36]([CH3:38])=[CH2:37]>C1COCC1>[C:35]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[CH:8][CH:9]=1)(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: Cc1ccc(O)c(N=Nc2ccc(CCO)cc2)c1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCc1ccc(N=Nc2cc(C)ccc2O)cc1
Temperature: -20 °C
Reaction time: 20 h

Procedure:
In a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer and gas inlet was dissolved 8.21 g (32.0 mmol) 2-((4-(2-hydroxyethyl)phenyl)diazenyl)-4-methylphenol in 200 ml anhydrous THF. ˜50 mg 4-Methoxyphenol (50 mg, Aldrich) was added followed by 20.1 g (254 mmol) anhydrous pyridine. The reaction mixture was cooled to −20° C. and 4.75 g (45.4 mmol) methacryloyl chloride was added dropwise. The reaction mixture was stirred for 1 hour at −20° C. and 20 hours at ambient temperature. The solid was filtered and 200 ml diethyl ether was added to the filtrate. Ethyl acetate (100 ml) was also added to aid in the separation. The organic layer was washed with 0.5 N HCl, and then dried over magnesium sulfate and then filtered. The solvent was removed under removed pressure and the crude product was recrystallized in ethanol to give an orange solid which was rinsed with cold ethanol and dried overnight under high vacuum at room temperature to afford 3.1 g (30%). 1H NMR (CDCl3) delta: 12.67 (s, 1H, Ar—OH), 7.82 (d, 2H, Ar—H), 7.73 (s, 1H, Ar—H), 7.38 (d, 2H, Ar—H), 7.15 (d, 1H, Ar—H), 6.93 (d, 1H, Ar—H), 6.08 (s, 1H, vinyl-H), 5.56 (s, 1H, vinyl-H), 4.41 (m, 2H, CH2OCO), 3.07 (m, 2H, Ar—CH2), 2.38 (s, 3H, Ar—CH3), 1.93 (s, 3H, C═C—CH3).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:9]([C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH2:8][CH2:7][N:6]2[C:19]=1[C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[CH3:2].B.C1COCC1.C(O)(=O)C.CO>O1CCCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[N:9]([C:10]3[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=3[CH3:16])[CH2:8][CH2:7][N:6]2[C:19]=1[CH:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCC=C(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: B
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 0 °C

Procedure:
6-Ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole (0.013 g, 0.000037 mol) in anhydrous tetrahydrofuran was treated with cold BH3-THF (0.15 mL 1.0 M in tetrahydrofuran), and the mixture was heated at reflux for 1.5 h. The mixture was cooled to 0° C., treated with glacial acetic acid (0.25 mL), heated at reflux for 1.5 h, re-cooled to 0° C., treated with 1.5 mL methanol, and heated again at reflux for 1 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between 2.5 N NaOH and ether. The organic phase was washed with water and brine, and was then dried over anhydrous Na2SO4 and evaporated to give a pale yellow oil. The crude product was chromatographed on silica, eluting with 15% ethyl acetate/hexanes to give a glassy solid. LC/MS: tR=1.81 min., (MH+)=354.30.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[CH2:17]O.O=S(Cl)Cl.[CH:23]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(CC)CC>C(Cl)Cl>[CH:23]1([N:28]2[CH2:29][CH2:30][N:31]([CH2:17][C:3]3[NH:4][C:5]([C:7]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:10]=[CH:9][CH:8]=4)=[N:6][C:2]=3[CH3:1])[CH2:32][CH2:33]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1nc(-c2cccc3ccccc23)[nH]c1CO
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2cccc3ccccc23)[nH]c1CN1CCN(C2CCCC2)CC1

Procedure:
(5-Methyl-2-naphthalen-1-yl-3H-imidazol-4-yl)-methanol (40 mg) is treated with SOCl2, followed by N-cyclopentylpiperazine (60 mg) and Et3N (0.04 ml) in CH2Cl2 (2 ml). The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid. LCMS 375.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NC(=O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanoic acid (0.3 g, 0.95 mmol) in dichloromethane (10 mL) were added methanesulfonamide (90 mg, 0.95 mmol), N,N-dimethylaminopyridine (0.12 g, 0.95 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mL, 0.95 mmol), and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure to give the title compound (0.10 g, yield 30%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:16])=O.CCCCCC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]([Cl:16])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Cl)c1cccc2[nH]ccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
32.2 g (0.2M) dry indol-4-yl carboxylic acid are suspended in 150 ml absolute methylene chloride. 26 ml (0.3M) oxalyl chloride are added to the stirred mixture at 20° over 30 minutes. Gas evolution results. The mixture is stirred for 31/2 hours at 20° C. 150 ml Hexane are added. The mixture is stirred for another 20 minutes and the resultant heading compound filtered off, washed with methylene chloride/hexane 1:1 dried at 20° in a vacuum to give beige crystals, which are used further without purification.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C(=O)C.O>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:21]3[C:17](=[O:27])[C:18]4[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:20]3=[O:22])([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1C(=O)c3ccccc3C1=O)O2
Yield: 56.8 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (2.0 g) and potassium phthalimide (2.2 g) in N,N-dimethylacetamide (20 mL) was refluxed under nitrogen gas for 3 hours. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to provide 1.4 g of the title compound. Yield 56%.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:35][CH2:34]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.8 g of [2-(4-chlorophenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4chlorophenyl)ethyl]piperazine having a melting point of 82°-83°.
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)CCCO)C1C=CC=CC=1.[C:23]([O:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:29][CH2:30][OH:31])(=[O:25])[CH3:24]>>[C:23]([O:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:29][CH:30]=[O:31])(=[O:25])[CH3:24]
Reactant: CCCCC[C@@H](CCCO)OC(C)=O
Agent: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Product: CCCCC[C@@H](CCC=O)OC(C)=O

Procedure:
This compound is prepared essentially by the method as described in Example 5, Step B-6, except that the 4-benzyloxy-5-(4-fluorophenoxy)pentanol is replaced by 4(S)acetyloxy-1-nonanol. This method provides the title compound as an essentially colorless oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:29][C:30]([NH2:34])=[N:31]2)=[CH:26][CH:25]=1>>[NH2:34][C:30]1[CH:29]=[C:28]([N:35]2[CH2:36][CH2:37][N:38]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:39][CH2:40]2)[C:27]2[C:32](=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:31]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, 7-chloro-4-aminoqunoline, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 427 (M++1). 1H NMR (DMSO-d6) δ 3.0–3.2 (m, 4H), 3.6–3.9 (m, 4H), 6.2–6.3 (s, 1H), 6.4–6.6 (s, H), 7.05–7.2 (m, 1H), 7.35–7.4 (m, 1H), 7.4–7.5 (d, 2H), 7.7–7.8 (d, 1H), 8.2–8.35 (d, 2H).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH2:15])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31].O>C(Cl)Cl>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH:15][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline (1 g, 3.86 mmol), triethylamine (0.65 mL, 4.63 mmol) in CH2Cl2 was treated dropwise with methoxyacetyl chloride (0.5 g, 4.63 mmol), allowed to come to room temperature, stirred for 2 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (1/1) as the eluting solvent gave N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-2-methoxyacetamide as a yellow solid (1.25 g, 94% yield), MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 3.30 (s, 3H), 3.97 (s, 2H), 7.2 (m, 3H), 7.3 (m, 2H), 7.6 (m, 3H), 7.9(t, J=1.7 Hz, 1H), 9.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.ClC(OCC)=O>CN(C=O)C.C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a stirred solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.28 g) in DMF (30 ml) was added dropwise a solution of mixed anhydride prepared from N-t-butoxycarbonylglycine (3.912 g), triethylamine (2.371 g) and ethyl chloroformate (2.425 g) in methylene chloride (15 ml) with stirring under ice-cooling. The stirring was continued for 1 hour at the same temperature. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and evaporated in vacuo. The residue was dissolved in methanol (12 ml) and conc. ammonia (1.5 ml) was added thereto. After stirring for 2 hours at room temperature, the resulting precipitates were collected by filtration, washed with methanol, and dried to give 6-[4-[N-(t-butoxycarbonyl)glycylamino]phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.74 g).