Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH2:29]([NH:36][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1NCc1ccccc1
Yield: 27.2 %

Procedure:
A solution of 100 mg of 4-fluoro-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide (Example 41), 29 mg of benzylamine, and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated to 100° C. for 6 h. After the addition of water, extraction with EA, and chromatographic separation, 33 mg of 4-benzylamino-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide were obtained.
Reaction SMILES: I[C:2]1[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:21]#[C:22][C:2]2[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: CSc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C#Cc2ccc(N)nc2)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (2.1 mmol) 5-iodo-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine, 1.5 g (12.4 mmol) 5-ethynyl-2-amino-pyridine, 39 mg (0.21 mmol) CuI, 145 mg (0.21 mmol) PdCl2(PPh3)2 and 2.9 mL triethylamine in 15 mL dry DMF. Yield after purification by RP-HPLC: 427 mg (52%).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:45]>O1CCOCC1.CCOCC>[ClH:45].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 88 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (56.3 mg, 94.2 μmol) in 4 M HCl in dioxane (471 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (44.4 mg, 88%) as a white solid. MS m/z 498 (MH)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[Cl:17])[C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(Cl)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde and 2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of 2-(4bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of 3-amino-N-ethylpiperdine (2.6 g, 0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol to give 4.9 g (62%) of a white solid, mp 190°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=O.[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([CH2:22][C:23](O)=[O:24])(=[O:21])=[O:20])=[CH:16][C:15]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([C:22]2[C:23](=[O:24])[O:11][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:20])=[O:21])=[CH:16][C:15]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2cc(S(=O)(=O)Cc3ccc(OC)c([N+](=O)[O-])c3)c(=O)oc2c1
Yield: 75 %

Procedure:
A solution of 4-methoxysalicylaldehyde (1 mmol) and 2-(4-methoxy-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 75% yield of the title compound; m.p. 250-252° C.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][CH:8]([CH2:11]O)[CH2:9][OH:10]>>[CH2:2]([CH:1]1[O:10][CH2:9][CH:8]([CH3:11])[CH2:7][O:6]1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(CO)CO
Reactant: CC(C)CC=O
Product: CC(C)CC1OCC(C)CO1

Procedure:
2-isobutyl-5-methyl-1,3-dioxane was prepared on a laboratory scale by acid catalysed condensation of isovaleraldehyde and 2-methylpropane-1,3-diol using a 1 litre 3 necked flask equipped with a Dean and Stark condenser, a thermometer and a mechanical stirrer. The reaction scheme is shown in FIG. 1.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:24])[CH3:23].CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:24][CH2:22][CH3:23])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCN
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: ClCCl
Product: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 90 mg, 0.19 mmol) and ethylamine (2.5 ml, 70% w/v in water). Yield 58.3 mg (0.13 mmol, 70%), mp 205–207÷C, Rƒ 0.15 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.97 (t, 1H, J=5.15 Hz, NH), 6.89 (s, 2H, NH2), 5.79 (d, 1H, J=7.56 Hz, H-1′), 5.65–5.61 (m, 1H, OH-2′), 5.30 (d, 1H, J=6.18 Hz, OH-5′), 5.18 (d, 1H, J=3.77 Hz, OH-3′), 4.55 (q, 1H, J=6.17 Hz, H-2′), 4.08–4.04 (m, 1H, H-3′), 3.94 (bs, 1H, H-4′), 3.65–3.61 (m, 2H, H-5′), 2.49 (m, 2H, CH2), 1.16 (t, 3H, J=7.21 Hz, CH3); MS m/z 437 (M+H)+; Anal. (C12H17IN6O4) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[CH3:8])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:5]2[S:6][C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[N:4]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCc1nc(N)sc1C
Product: CCc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1C
Yield: 12 %

Procedure:
The title compound was prepared from 4-ethyl-5-methyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish foam, 40 mg (12% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0271).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=2[S:21](Cl)(=[O:23])=[O:22])=[N:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:13]=1
Reactant: Cc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a stirred solution of 2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (300 mg, 0.78 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (194 mg, 1.3 mmol) in 5 mL of ACN was added pyridine (1.26 mL, 9.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (318 mg, yield 82%). MS calcd for (C19H16BN4O6F3S): 496.2, MS found (ESI negative): (M−H)−=495.1. 1H NMR (DMSO-d6) δ (ppm): 11.5 (s, 1H), 10.5 (s, 1H), 9.20 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (s, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.86 (s, 2H), 4.59 (s, 2H), 2.40 (s, 3H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:46]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][NH2:54])=[CH:48][CH:47]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8]([C:9](=[O:11])[NH:54][CH2:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:47][CH:48]=1)[CH2:12][CH2:13][CH2:14][S:15][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 29 (200 mg, 0.41 mmol) and HOBt (66 mg, 0.49 mmol) in DMF (2 mL), were added 4-biphenylethylamine (124 mg, 0.62 mmol) and DIC (78 μL) respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, with a saturated sodium hydrogen carbonate solution, and again with brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed using 30% ethyl acetate in hexanes. 1H-NMR (CDCl3, 400 MHz: 1.55(s, 9H); 1.41-1.57(m, 2H); 2.04-2.28(m, 6H); 2.54(m, 1H); 2.80(m, 2H); 3.45-3.55(m, 2H), 5.66(m, 1H); 7.19-7.57(m, 24H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CC#N>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:10])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NS(=O)(=O)c1cc(F)cc(F)c1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 45829.8 %

Procedure:
To a solution of 3,5-difluorobenzenesulfonamide (154 g, 0.797 mol) in CH3CN (1 L) was added N,N-dimethylformamide dimethylacetal (224 mL, 1.67 mmol, 2.1 eq). After stirring 1 h, the reaction mixture was concentrated under reduced pressure. This material was triturated with Et2O and dried in vacuo to give N′-(3,5-difluorophenylsulfonyl)-N,N-dimethylformimidamide (190 g, 96%) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.44-7.38 (m, 2H), 6.98-6.91 (m, 1H), 3.17 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CC(Oc2nccnc2Cl)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and tert-butyl (3-hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+1): 300 calc. for C13H18ClN3O3 299.
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:11][C:10]=1[OH:29])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][O:13][C:12]1[CH:27]=[CH:28][C:9]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:31]([C:32]([O:34][CH3:35])=[O:33])[O:29][C:10]=2[CH:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 54.9 %

Procedure:
A mixture of 4-(4-benzoyl-3-hydroxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (54.93 g), methyl bromoacetate (32.88 g), potassium carbonate (19.76 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, 1,8-diazabicyclo[5.4.0]-7-undecene (21.77 g), and toluene (750 mL) was heated under reflux for 20 hrs with azeotropic removal of water. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:8, v/v) to give methyl 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-carboxylate as colorless crystals (34.36 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=[O:12].Cl>>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:4]([CH3:3])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1N NaOH (86 ml) was added to a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)benzoate (Step A, 16.31 g, 57.4 mmol) in absolute alcohol (150 ml). After 3 hours of stirring at room temperature, the reaction mixture was acidified with 1M HCl and concentrated in vacuo. The organic residue was taken into chloroform and washed with 1N HCl, dried over Na2SO4, filtered, concentrated and purified by flash chromatography using chloroform:methanol (95:5 spiked with acetic acid) as elutent.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[OH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:1]=1
Reactant: CCOC(=O)C(C)Br
Reactant: OCc1ccc(O)cc1
Product: CCOC(=O)C(C)Oc1ccc(CO)cc1
Yield: 79.7 %

Procedure:
Using as starting materials 1.00 g of p-hydroxybenzyl alcohol and 1.61 g of ethyl 2-bromopropionate, 1.44 g of ethyl 2-[p-(hydroxymethyl)phenoxy]propionate was obtained in a manner similar to Reference Example 2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].O.[NH2:14][NH2:15]>C(O)C>[NH2:2][C:1]1[C:3]2[C:11](=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[NH:15][N:14]=1
Reactant: NN
Reactant: N#Cc1cc(C(=O)O)ccc1F
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 3-cyano-4-fluorobenzoic acid (980.0 mg, 5.94 mmol) in ethanol (6 mL), was added hydrazine hydrate (0.89 mL, 17.8 mmol). The reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature and ethanol was removed under reduced pressure. The resultant yellow oil was taken up in water (50 mL) and basified with 1 N aqueous sodium hydroxide (5 mL). The solution was washed once with ethyl acetate (25 mL). The aqueous phase was acidified to pH=3 with 6 N aqueous hydrochloric acid and was allowed to stir at room temperature for 1 hour. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (612 mg, 48%) as a pink solid. +ESI (M+H) 178.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.42-8.47 (m, 1H), 7.76 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2>N1C=CC=CC=1>[Br:1][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:18][CH:17]=2
Reactant: Clc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1ccc2ncc(Br)cc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The synthesis was done by the same procedure as that of J. J. Eisch (J. Org. Chem. Vol. 27, p.1318, 1962). Bromine (79 μl) and carbon tetrachloride (2 ml) were added to 6-chloroquinoline (250 mg) and stirred at 90° C. for two hours. Pyridine (123 μl) was added to the reaction solution and stirred at the same temperature for 16 hours. The reaction solution was concentrated and purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (250 mg).
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl[CH2:20][C:21]#[C:22][CH2:23][S:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CO>[C:26]([O:28][CH3:29])(=[O:27])[CH2:25][S:24][CH2:23][C:22]#[C:21][CH2:20][S:18][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)CSCC#CCCl
Reactant: CCCCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
460 μl of a 30% solution of sodium methoxide in methanol were added to a solution of 665 μl of tetradecanethiol in a 5 ml methanol/2 ml THF mixture, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then 0.47 g of methyl 7-chloro-3-thia-5-heptynoate in 5 ml of methanol was added, under an inert atmosphere. The mixture was maintained under stirring for 8 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The wax thus obtained was chromatographed on a silica gel column (CH2Cl2) providing 1.05 g of methyl 3,8-dithia-5-docosynoate in the form of an oil. (Quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([O:19][CH3:20])=[C:7]2[C:3]=1[C:4]1[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:5]=1[N:6]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].[CH3:35]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH3:35])[C:8]([O:19][CH3:20])=[C:7]2[C:3]=1[C:4]1[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:5]=1[N:6]2[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: CI
Reactant: COc1c(NC(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N(C)C(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To a solution of Compound 249 (610 mg, 1.2 mmol) in dry DMF (3 mL) was added NaH (60 mg, 1.51 mmol) at 0° C. and the mixture was stirred for 20 min. To this ice cold reaction mixture was added MeI (0.72 ml, 1.44 mmol, 2 M solution) and stirred for another 30 min. at 0° C. Slowly the temperature was raised to room temperature and stirred for an additional hour. Reaction was quenched with water and extracted with ether, washed with brine, dried over Na2SO4 and finally purified flash chromatography to furnish Compound 250 (468 mg, 75%).