Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[CH2:40][C@@H:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[O:38][C:37]2=[O:50])=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C@H:39]1[O:38][C:37](=[O:50])[N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:51]3[N:52]=[C:53]([NH2:56])[S:54][CH:55]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[CH2:40]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Yield: 53.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((R)-5-(((tert-butoxycarbonyl)amino)-methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (725 mg, 0.794 mmol), DCM (8.0 mL) and TFA (3.7 mL, 48.0 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (231 mg, 52%) as a white powder. LCMS: Rt=0.41 min, m/z=548.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J=8.8 Hz, 1H), 8.00 (t, J=5.8 Hz, 3H), 6.83 (s, 1H), 5.22 (dd, J=8.8, 5.9 Hz, 1H), 4.68 (tdd, J=9.0, 5.8, 3.4 Hz, 1H), 4.24 (ddd, J=9.3, 5.9, 3.6 Hz, 1H), 3.75 (t, J=8.8 Hz, 1H assumed; obscured by water), 3.61 (dd, J=8.7, 5.8 Hz, 1H assumed; obscured by water), 3.41 (dd, J=14.7, 9.0 Hz, 1H), 3.30 (dd, J=14.7, 3.7 Hz, 1H), 3.25-3.05 (m, 2H), 1.40-1.27 (m, 4H). 1H NMR (400 MHz, D2O) δ 7.18 (d, J=2.4 Hz, 1H), 5.45 (d, J=5.8 Hz, 1H), 5.02-4.93 (m, 1H), 4.70 (ddd, J=9.2, 5.8, 3.7 Hz, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.78 (dd, J=15.0, 9.0 Hz, 1H), 3.60-3.56 (m, 1H), 3.54 (dd, J=11.3, 3.6 Hz, 1H), 3.40 (s, 1H), 3.38 (d, J=2.0 Hz, 1H), 1.57-1.49 (m, 2H), 1.49-1.40 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30])=[O:4]>CO>[OH:4][CH2:3][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CCO)ccc21
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
Sodium borohydride (0.027 g) was added to a stirred solution of methyl 4-[5-(formylmethyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.54 g) in methanol (15 ml) under a nitrogen atmosphere. After 30 min, the solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water (twice), brine, and then dried (MgSO4) and evaporated. The product was purified by flash chromatography, eluting with 7:3 hexane:ethyl acetate, to give methyl 4-[5-(2-hydroxyethyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.35 g, 65%) as an oil: partial NMR (300 MHz, DMSO-d6): 0.80(t, 3H, CH3), 1.70(m, 2H, CH2), 2.74(t, 2H, CH2), 3.56(t, 2H, CH2), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.03(m, 4H, NCH2, ArCH2Ar').
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-])=O)[C:4]=1[N+:13]([O-])=O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([NH2:10])[C:4]=1[NH2:13]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CCO
Product: COc1ccc(C)c(N)c1N
Reaction time: 8 h

Procedure:
3-Methoxy-6-methyl-benzene-1,2-diamine was synthesized by suspending 3.3 g of 1-methoxy-4-methyl-2,3-dinitro-benzene (Can. J. Chem. 65, 1233-1240, 1987) in 100 mL EtOH, evacuating 3 times with N2 and addition of 450 mg of 10wt % Pd/C. The reaction mixture was stirred under a H2 atmosphere (balloon) overnight. Filtration over a pad of celite and washing with 100 mL EtOH yielded after concentration in vacuo 2.2 g of the desired compound as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:24][CH2:25][CH2:26]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:26][CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCc1ccccc1
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(OCCOCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A mixture of 1-bromo-2-hydroxy-4-methoxy benzene (68.3 g, 0.336 moles), anhydrous potassium carbonate (51.2 g 0.37 moles) and 0.5 L of N,N-dimethylformamide was heated to 65° C. Benzyloxyethylbromide (76.0 g, 0.353 moles) was added dropwise over 0.5 hr. After stirring for 1.5 hr. at 65° C., the reaction mixture was cooled and filtered. The filtrate was diluted with 1 L of deionized water, and extracted with 3×0.5 L ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Distillation gave 93 g (83%) of product as a yellow liquid (b.p. 170°-175° C., 0.5 mm).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1ccccc1Cl
Yield: 69.7 %

Procedure:
Similarly, N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-chlorophenyl)carboxamide (154) (16.1 mg, yield 69.7%, purity>90%) was prepared from 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) and 2-chlorobenzoyl chloride (11 μl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:16]([OH:18])=O)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH:28][C:16]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]2)=[O:18])[CH3:27])=[CH:22][CH:21]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC(=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(=O)CC1)c1ccc(F)cc1

Procedure:
1-(tert-Butoxycarbonylamino)-4-oxocyclohexanecarboxylic acid (750 mg) was coupled with (R)-1-(4-fluorophenyl)ethanamine using the HATU procedure as described in Example 1. The crude was chromatographed with gradient elution 15-80% ethyl acetate in heptane to yield the title compound (900 mg). MS MH+ 379.3
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 68 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azetidin-1-yl-2-chloroethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][NH:29][CH3:30]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:29]([CH3:30])[CH3:28])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: CNC
Solvent: CO
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 12.90 g (0.025 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13(b)] and 11 ml of 33% ethanolic dimethylamine solution in 250 ml of methanol is stirred for 7 hours at room temperature. The reaction solution is thereupon concentrated in vacuo; water is added to the residue and the whole is extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The amorphous residue is dissolved in 130 ml of ether; the solution is allowed to stand and the reaction product then crystallises out. It is filtered off with suction and washed with ether. After drying there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 131°-134°.
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[C:6]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH2:40]([O:39][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:18]=2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:7]=1)[C:3]([OH:50])=[O:2])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1

Procedure:
A solution of 1.75 g (2.57 mmol) of 3-(decyloxy)-5-[[6-[2,3-bis (phenylmethoxy)phenyl]hexyl]oxy]benzoic acid methyl ester and 1.3 ml (7.8 mmol) of 6N NaOH in 75 ml of methanol and 25 ml of dioxane was stirred at reflux under argon for 24 hours. The usual workup gave 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]benzoic acid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([N:22]1[C:26](=[O:27])[CH2:25][S:24][C:23]1=[S:28])[CH3:21].C(N(CC)CC)C>C(O)C>[CH2:20]([N:22]1[C:26](=[O:27])[C:25](=[C:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:8]2)[S:24][C:23]1=[S:28])[CH3:21]
Reactant: CCN1C(=O)CSC1=S
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=C2C=C(N3CCCC3)CC(C)(C)C2)SC1=S

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.1 g., 0.01 mol.), 3-ethylrhodanine (1.6 g., 0.011 mol.) and triethylamine (3.1 ml.) are dissolved in ethanol (20 ml.) and heated at reflux for 10 minutes. After chilling, the solid is collected on a filter, rinsed with ethanol and dried. After one recrystallization from pyridine/methanol, the yield of purified dye is 2.2 g. (65%), m.p. 234°-235°C. with decomposition. This dye is an excellent spectral sensitizer for photographic silver halide emulsions in the minus blue region of the spectrum as set forth in Table 2 hereinafter.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC1C=C(O)C=CC=1C#N.C(Br)CCC.C(=O)([O-])[O-].[K+].[K+].CN(C1C=CC=CN=1)C.[F:46][C:47]1[C:52]([F:53])=[C:51]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH:50]=[CH:49][C:48]=1O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[C:52]([F:53])[C:47]=1[F:46])=[O:5]
Reactant: CCCCOc1ccc(C(=O)O)c(F)c1
Reactant: CCCCCCCCc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: N#Cc1ccc(O)cc1F
Solvent: CCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OC(=O)c2ccc(OCCCC)cc2F)c(F)c1F

Procedure:
0.1 mol of 2-fluoro-4-butyloxybenzoic acid (prepared from 3-fluoro-4-cyanophenol by alkylation with butyl bromide/potassium carbonate in dimethylformamide and subsequent hydrolysis of the nitrile via the imido ester), 0.01 mol of dimethylaminopyridine and 0.1 mol of 2,3-difluoro-4-octylphenol are initially introduced into 150 ml of methylene chloride, a solution of 0.1 mol of dicyclohexylcarbodiimide in 30 ml of methylene chloride is added dropwise at 10°, while stirring, and the mixture is then subsequently stirred at room temperature for 15 hours. The mixture is filtered over silica gel and the solvent is evaporated to give 2,3-difluoro-4-octylphenyl 2-fluoro-4-butyloxybenzoate as the residue.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([SH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]I)[CH:26]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC>[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][S:11][C:6]3[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:26]=2)[CH:19]=1
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(Cc2cccc(CI)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCc1c(SCc2cccc(Cc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Yield: 84.9 %

Procedure:
Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (132 mg, 0.63 mmol), 3-(3-Iodomethyl-benzyl)-benzoic acid methyl ester (230 mg, 0.63 mmol), and cesium carbonate (410 mg, 1.26 mmol) in 2-butanone (6 ml) at room temperature under argon for 20 hours. Pour the mixture into water (60 ml) and extract with ethyl acetate (2×30 ml). Combine the organic extracts and wash with water, brine, then dry over sodium sulfate, filter and concentrate. Purify the crude product via silica chromatography eluting with 1:4 ethyl acetate:hexanes to give the title compound (240 mg, 85%). MS (m/z) 447 (M−H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=1[F:18].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.CCOCC>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[F:18]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.4 %

Procedure:
A cooled (0° C.) suspension of lithium aluminium hydride (88 mg; 2.3 mmol) in anhydrous THF (10 mL) was treated dropwise with a solution of methyl 4-bromo-3-fluorobenzoate (Combi-Blocks; 300 mg; 1.29 mmol) dissolved in anhydrous Et2O (10 mL), and the reaction mixture was stirred at RT for 2 days. The reaction mixture was treated with a saturated aqueous solution of sodium thiosulfate. The organic phase was separated, dried over MgSO4, filtered and concentrated to dryness affording the title compound as a yellow liquid (247 mg, 94%).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10]>>[OH:5][CH2:4][C@@H:3]([CH3:6])[CH2:2][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:24])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CO)CCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)CO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (2R)-3-chloro-2-methyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=2)=[N:6]1.[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]3[NH:21][C:26](=[O:27])[NH:20][C:17]3=[N:18][CH:19]=2)=[N:6]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: c1ccncc1
Product: O=c1[nH]c2ncc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
40 mg (0.12 mmol) of the compound from example 52A were initially charged in pyridine (5.0 ml), then 39 mg (0.13 mmol) of bis(trichloromethyl) carbonate were added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was concentrated, admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 9 mg (20% of theory) of the title compound in solid form.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1
Reactant: COC(=O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Reactant: Cn1nc(C(F)(F)F)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(Cl)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of tri-n-butylphosphine (0.193 mL), methyl(4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetate (150 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (102 mg) and THF (5.0 mL) was added ADDP (195 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated in vacuo. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (205.9 mg). The solid was crystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[OH:29])[CH2:22][CH2:21]4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41]>C(#N)C>[Cl:41][CH2:40][CH2:39][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1([NH:19][C:15]2[C:14](=[O:30])[N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:31])[CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:21]1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Temperature: 95 °C

Procedure:
To N-Cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 167d, 0.34 g) in acetonitrile (5 mL) under nitrogen was added potassium carbonate (1.13 g) followed by 1-bromo-2-chloroethane (1.35 mL) and the reaction heated at 95° C. for 15 h. After cooling to rt the mixture was filtered through celite, and the solid cake washed with further acetonitrile. The filtrates were collected and the solvents removed in vacuo to give the subtitle product as a brown-orange solid (0.373 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:12][Mg]Br.C(OCC)C.Cl>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: Brc1cncc2ccccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cncc2ccccc12
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 4-bromoisoquinoline (1 g, 4.81 mmol) in THF (20 ml) was added [1,3-Bis(diphenylphosphino)propane]nickel(II)chloride (0.026 g, 0.048 mmol) followed by methyl magnesium bromide in diethyl ether (1.923 ml, 5.77 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mixture was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (5% ethyl acetate in pet ether) to get desired compound (0.6 g, 78%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.15(s, 1H), 8.37 (s, 1H), 8.13-8.11 (d, J=8 Hz 1H), 8.05-8.03 (d, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.71 (t, J=8 Hz, 1H) 2.59 (s, 3H); GC-MS: MS m/z 143 (M+).