Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1Br.C(N(CC)CC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:30]#[C:29][C:26]1[CH:25]=[CH:24][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccncc1C#Cc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-isonicotinic acid methyl ester (648 mg, 3.00 mmol) in DMF (6 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (210 mg, 0.30 mmol), copper(I) iodide (17.1 mg, 0.090 mmol), triethylamine (1.25 ml, 9.00 mmol) and 1-tert-butyl-4-ethynyl-benzene (570 mg, 3.60 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 3 hours. The reaction mixture is allowed to cool to room temperature and reduced in volume under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester as brown oil; HPLC/MS 2.28 min (A), [M+H] 294.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[OH-].[Na+].C([O-])=O.[Na+]>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Br-].[Pd].O>[CH3:10][C:4]1[CH:3]=[C:2]([C:2]2[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=2)[CH:8]=[C:7]([CH3:9])[C:5]=1[NH2:6]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=C[O-]
Solvent: O
Product: Cc1cc(-c2cc(C)c(N)c(C)c2)cc(C)c1N

Procedure:
Compound 1a was prepared using the procedure described in P. Bamfield and P. M. Quan, Synthesis, 1978, 537 using 4-bromo-2,6-dimethylaniline (10.00 g, 50 mmol), CTAB (2.00 g, 5.5 mmol, 0.11 eq.), 5% palladium on charcoal (0.80 g, 50% paste), sodium hydroxide (21.1 ml, 8.0M, 0.169 mol) and sodium formate (2×3.40 g, 100 mmol, 2 eq.) in water (30 ml).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Yield: 56.4 %

Procedure:
By using 300 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate and 289 mg of ethyl 4-bromobutyrate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 201 mg of methyl 4-(2-{4-[({2-[(3-{[cyclopropyl(4-ethoxy-4-oxobutyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:25])[CH3:24])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[C:23]([CH3:25])([O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15](=[O:31])[NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:17]=1)[CH3:24])[CH3:30]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Reaction time: 5 h
Yield: 71.8 %

Procedure:
2.08 g (5.0 mmol) of 4-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester was dissolved under argon in 80 mL of MeCl2; to the stirred solution, 3.66 mL (5.46 g=10 eq.) of TFA was added drop by drop and stirring continued at rt for 5 h. Then, the reaction mixture was evaporated i.V., the residue was dissolved in MeCl2 and water, the pH was adjusted to ˜10 with sodium carbonate solution and the mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 1.20 g of the title compound as colorless oil. MS: 335.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:18]=O)[CH2:8][C:9]=1[NH:10]2.C([O-])(=O)C.[NH4+:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>C(Cl)Cl>[NH2:24][CH2:18][CH:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:2]=3[Br:1])[NH:10][C:9]=2[CH2:8]1
Reactant: [NH4+]
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C=O)CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reaction time: 0.17 h
Yield: 13 %

Procedure:
Step 3 A solution of crude 5-bromo-2-formyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (1 g, 3.11 mmol) in DCM (20 mL) was treated with ammonium acetate (3.60 g, 46.7 mmol) and sodium triacetoxyborohydride (0.990 g, 4.67 mmol) at rt and stirred for 10 min. THF (2 mL) was added to try to dissolve the starting material, but no reaction was observed after 1 h. The mixture was concentrated and the residue was dissolved in DMSO (10 mL). Additional sodium triacetoxyborohydride (500 mg) was added and the mixture was stirred at rt overnight. The mixture was diluted with water and the precipitate was removed by filtration. The filtrate was treated with 1 M aqueous sodium hydroxide and extracted three times with EtOAc. The combined organic phases were washed with water, dried and concentrated to provide 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (130 mg, 13%), used without further purification. Mass spectrum m/z 322, 324 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-hydroxy-4-biphenyl carbonitrile and 3-Iodomethyl-1-(4-methoxy-benzoyl) pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (124 mg, 71%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Br:19]N1C(=O)CCC1=O>O1CCCC1>[Br:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol) and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (464 mg, 1.35 mmol, 50% yield) as an orange oil: LCMS (ES) m/e 343, 345 (M, M+2)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][CH3:10])[N:6]=[CH:7][N:8]=1.[C:11]1([N:17]2[C:21]3[NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:20]=3[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:9]([N:5]1[C:4]([CH2:3][O:30][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:20]3[CH:19]=[N:18][N:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:21]=3[N:22]=2)=[N:8][CH:7]=[N:6]1)[CH3:10]
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)c2ccccc12
Reactant: CCn1ncnc1CCl
Agent: Cl
Product: CCn1ncnc1COc1nc2c(cnn2-c2ccccc2)c2ccccc12
Yield: 76.5 %

Procedure:
Prepared as for Example 1, step c), using 3-chloromethyl-2 -ethyl-2H-[1,2,4]triazole hydrochloride (0.10 g, 0.55 mmol) and 3,4-dihydro-3-phenyl-5H-pyrazolo[3,4-c]isoquinolin-5-one (0.095 g, 0.36 mmol) to give the title compound (0.102 g, 76%) as an off-white powder, m.p. 147-148° C. Found: C, 66.49; H, 4.83; N, 22.16. C21H18N6O.0.5(H2O) requires C, 66.48; H, 5.05; N, 22.15%. δH (400 MHz; CDCl3) 1.47 (3H, t, J=7), 4.30 (2H, q, J=7), 5.82 (2H, s), 7.36 (1H, dd, J=8 and 7), 7.51-7.58 (3H, m), 7.83 (1H, dd, J=8 and 7), 7.96 (1H, s), 8.16 (1H, d, J=8), 8.22 (2H, d, J=8), 8.30 (1H, d, J=8), 8.42 (1H, s); m/z (ES+) 371 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][N:9]([C:18]1[S:19][CH:20]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]2)[N:22]=1)[CH2:10][C:11]1[S:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=1)(C)(C)C.[OH-].[Na+].C1COCC1>CO>[C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([C:21]2[N:22]=[C:18]([N:9]([CH2:10][C:11]3[S:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8][CH2:7][C:6]([OH:33])=[O:5])[S:19][CH:20]=2)[CH2:24][CH2:25]1)([CH3:31])([CH3:32])[CH3:30]
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(CN(CCC(=O)O)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (72 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) to obtain 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (108 mg, 0.220 mmol) following a method analogous to General Procedure C (and similar to the procedure found in Example 5). Hydrolysis of this ester following a method analogous to General Procedure G1 using 1 N NaOH (aq) solution (2 mL), THF (1 mL) and MeOH (1 mL) gave 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid (37 mg, 0.085 mmol). LC-MS m/z: 435 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC=CCN
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 32, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]1.Br.Br.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+].[I-].[K+].Cl>C(O)CCC.C(O)C.CCOCC>[ClH:1].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]2)[CH2:26][CH2:25]1
Reactant: CC(C)N1CC(CCCCCl)OC1=O
Reactant: Oc1ccccc1N1CCNCC1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCCCO
Solvent: CCOCC
Product: CC(C)N1CC(CCCCN2CCN(c3ccccc3O)CC2)OC1=O
Yield: 46 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-(1-methylethyl)-2-oxazolidinone (10.4 g, 0.0474 mol), 1-(2-hydroxyphenyl)piperazine dihydrobromide (16.12 g, 0.0474 mol), sodium bicarbonate (15.96 g, 0.190 mol) and potassium iodide (1.0) in n-butanol (350 mL) gave an oil. The oil was dissolved in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ether and filtration gave a solid which was dried under high vacuum at 70° C. to give 9.47 g (46% yield), mp 203°-207° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:12].[BH4-].[Na+].C([O-])(=O)C.[Na+].Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:22](OC)=[O:23]>C(O)C.C(O)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:21]2[S:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]=3[NH:1][C:22]2=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:27][CH:28]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: Nc1c(S)ccc2ccccc12
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 1-amino-2-naphthalenethiol (27.81 g) in ethanol (500 ml) is added sodium borohydride (11.35 g) at room temperature. The mixture is stirred for 20 minutes, and thereto is added dropwise acetic acid (200 ml) and is further added sodium acetate (24.6 g). To the mixture is further added dropwise methyl α-bromo-4-chlorophenylacetate (46.8 g), and the mixture is sitrred at room temperature under argon overnight. The reaction mixture is poured into ice water and the resulting precipitate is separated by filtration, washed, dried and recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (44.45 g, yield 82.6%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](Br)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Mg].Br[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCOc1cc(Br)c(OCCCCCCCC)cc1Br
Reactant: Brc1cccs1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1cc(-c2cccs2)c(OCCCCCCCC)cc1-c1cccs1
Yield: 45 %

Procedure:
A solution of 1,4-dibromo-2,5-dioctyloxybezene (6.580 grams, 13.365 mmol) in 15 milliliters of anhydrous tetrahydrofuran (THF) was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.975 gram, 40.095 mmol) in 5 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 3.5 hours. Subsequently, the resulting mixture was added to a mixture of 2-bromothiophene (5.447 grams, 33.412 mmol) and [1,3-bis(diphenylphosphinoethane]dichloronickel (II) (0.350 gram, 0.663 mmol) in 45 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 24 hours. Thereafter, the reaction mixture was diluted with 200 milliliters of ethyl acetate, washed twice with water and then dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromatography on silica gel and recrystallization yielding 1,4-bis(2-thienyl)-2,5-dioctyloxybenzene as a light yellow crystalline product in 45 percent yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B was treated with 2-(4-chlorophenyl)acetyl chloride using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59 (s, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.11 (ddd, J=8.0, 1.3, 0.7 Hz, 1H), 7.99 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.91 (ddd, J=7.8, 7.2, 1.3 Hz, 1H), 7.33-7.48 (m, 5H), 4.42-4.46 (m, 2H), 3.67 (s, 2H), 1.37 (s, 9H); MS (APCI+) M/Z 343 (M−CO2tBu+H)+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[Br:9][CH2:10]CC(O)=O>>[Br:9][CH2:10][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4]
Reactant: O=C(O)CCBr
Reactant: CON(C)C(=O)CBr
Product: CON(C)C(=O)CCBr

Procedure:
In analogy to the procedure described in intermediate 1D, 3-bromopropionic acid gave the title compound as a light yellow liquid. MS: 195.9 (MH+, 1Br).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36][O:37]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: CCC(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=3.6, 0.8 Hz), 7.37 (dd, 1H, J=5.2, 1.2 Hz), 7.33-7.27 (m, 2H), 7.09-7.05 (m, 2H), 7.02-6.96 (m, 4H), 6.78-6.73 (m, 2H), 4.16 (t, 2H, J=6.6 Hz), 3.29 (s, 2H), 2.94 (t, 2H, J=6.6 Hz), 2.34 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:8][CH:9]=1)([O-])=O.NN>CO.[Ni]>[NH2:1][C:4]1[C:5]([NH:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(NCc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1nc(NCc2ccc(Cl)c(Cl)c2)ncc1N
Temperature: 60 °C

Procedure:
To a suspension of N-{2-[(5-nitro-2-{[(3,4-dichlorophenyl)methyl]amino}pyrimidin-4-yl)amino]ethyl}(tert-butoxy)carboxamide, prepared as described in Example 4, (1.5 g, 3.28 mmol) in MeOH (100 mL) was added hydrazine (1.8 mL of 65% v/v aq. solution, 33 mmol). The reaction mixture was heated to 60° C. Raney Ni was added in portions to keep evolution of nitrogen steady. After 1 h the reaction mixture was cooled to room temperature, catalyst filtered off, and the filter cake washed with MeOH. The resulting solution was concentrated and purified by chromatography eluting with MeOH/dichloromethane gradient to provide compound N-{2-[(5-amino-2-{[(3,4-dichlorophenyl)methyl]amino}pyrimidin-4-yl)amino]ethyl}(tert-butoxy)carboxamide as tan solid. Compound was used in the next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.CS(C)=[O:18].Cl.[N+](=C)=[N-]>>[O:18]=[C:2]1[CH:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: CS(C)=O
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(O)CCCC1C(=O)Nc2ccccc21
Yield: 89 %

Procedure:
Similar treatment of methyl 3-(3-indolinyl)propanoic [II: R1 =R3 =H, R2 =(CH2)2COOH] (0.93 g) with DMSO/HCl, followed by esterification with diazomethane and chromatography on silica gel, gave methyl 3-(2-oxo-3-indolyl)propanoate [III: R1 -R3 =H, R2 =(CH2)2COOMe] (0.89 g, 89%) as a yellow oil (Julian P. L., Printy H. C., J. Am. Chem. Soc. 1953;75:5301-5305 report mp 79°-80° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([O:40]C)=[O:39])=[C:32]([CH3:42])[CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][C:7]=1[CH3:43].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[CH3:1][O:2][C:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[C:32]([CH3:42])[CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][C:7]=1[CH3:43])=[O:44]
Reactant: COC(=O)COc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(OCC(=O)OC)c(C)c3)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)COc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(OCC(=O)O)c(C)c3)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of (E)(E) [4-(5-{4-[5-(4-methoxycarbonylmethoxy-3-methyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-2-methyl-phenoxy]-acetic acid methyl ester (example 17) (15 mg, 0.025 mmol) in ethanol (15 mL) and THF (5 mL) was added 1N sodium hydroxide (1.0 mL). After stirring at room temperature for 30 min., the reaction mixture was added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 10 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:32]([F:33])=[CH:31][C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:32]([F:33])=[CH:31][C:21]5[NH:22][CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc2c(cc1CNc1nccc(Nc3cc(C4CC4)[nH]n3)n1)ncn2C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Fc1cc2[nH]cnc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
A mixture of 108 (170 mg, 0.38 mmol) and TsOH.H2O (72 mg, 0.38 mmol) in MeOH (5 mL) and water (1 mL) was heated at reflux for 2 h. After solvent was removed in vacuo, the residue was purified by preparative HPLC to give 60 mg (43%) of I-28 as white solid.