Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27](O)=[O:28])=[CH:19][C:18]2=[O:30])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:28])=[CH:19][C:18]2=[O:30])[CH2:13][CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)O)c3ccccc32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)NS(C)(=O)=O)c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To 5 mL of tetrahydrofuran suspension containing 0.10 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 58 mg of 1,1′-carbonyldiimidazole was added, and stirred at 50° C. for 1 hour. The reaction mixture was cooled to the room temperature, then 84 mg of methanesulfonamide and 0.13 mL of 1,8-diazabicylo[5.4.0] undec-7-ene were added, and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, water was added, and adjusted to pH 4 with 1 mol/L hydrochloric acid. The resulting solid was filtered to afford 0.10 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-(((methylsulfonyl)amino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.[I-].[Na+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 1(a), the reaction is carried out with 28.7 g (0.11 mol) of 4-chloro-N-(4-methoxyphenyl)-benzamide, 4.5 g (0.18 mol) of sodium hydride, 36.7 g (0.13 mol) of 11-bromoundecanoic acid methyl ester, 100 cc. of dimethylformamide and 3 g (0.02 mol) of sodium iodide. Reaction time: 5 hours, reaction temperature: 80° C. The crude product is used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]([C:36]1[CH:51]=[CH:50][C:39]([O:40][C:41]2[C:42]([C:47](O)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:38][CH:37]=1)=[O:35].C(N(C(C)C)CC)(C)C.[C:61]1([CH2:67][CH2:68][NH2:69])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]=[C:26]1[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:40][C:41]2[C:42]([C:47]([NH:69][CH2:68][CH2:67][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:50][CH:51]=1)=[O:35]
Reactant: NCCc1ccccc1
Reactant: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (123 mg, 0.324 mmol) was added to a mixture of 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazine-2-carboxylic acid (106 mg, 0.294 mmol) and diisopropylethylamine (102 μL, 0.588 mmol) in DMF (1 mL) and the mixture was stirred at RT for 10 min. 2-Phenylethylamine (55.8 μL, 0.441 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was purified by chromatography on silica gel to deliver 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide as a white solid. MS (ESI, pos. ion) m/z: 464.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of sodium hydride (42 mg, 1.05 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (114 mg, 0.704 mmol) in DMF (1 mL) was added to the reaction mixture, and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 2-(10-methyl-2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)-1-(piperidin-1-yl)ethanone;
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([N:22]=[CH:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C=N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (5.0 g, the preparation of which was described in U.K. patent No. 1,511,187), glycine ethyl ester hydrochloride (2.59 g) and sodium hydroxide (0.75 g) in ethanol (100 mls) was refluxed for 7h. Filtration, evaporation, and chromatography gave the title compound (1.5 g). Recrystaisation of a small portion from ethyl acetate-pentane gave crystals of m.p. 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C@H:36]2[CH2:40][O:39][C:38](=[O:41])[NH:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C:10]([N:37]2[C@@H:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:40][O:39][C:38]2=[O:41])=[O:12])=[CH:13][CH:14]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: COc1ccc(CSCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
[(4-Methoxybenzyl)thio]acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1.0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex:EtOAc 8:2 then 1:1). This afforded the title compound.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:19][C:4]=2[S:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:33])[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:19][C:4]=2[S:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ncccn1
Solvent: ClC(Cl)Cl
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ncccn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
The procedure is as in Example 8, starting with 2-imino-3-[2-(2-pyrimidinylthio)ethyl]-6-trifluoromethoxybenzothiazoline (0.5 g) and meta-chloroperbenzoic acid (90% pure by weight) (1 g) dissolved in chloroform (20 cc). The reaction mixture is stirred for 1 hour at a temperature in the region of 20° C. and then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixture of ethyl acetate and methanol (95:5 by volume) as eluent. 2-Imino-3-[2-(2-pyrimidinylsulphinyl)ethyl]-6-trifluoromethoxybenzothiazoline (0.35 g), m.p. 120° C., is isolated.
Reaction SMILES: C(O)(=O)C.[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Br:17]Br>O>[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([Br:17])=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: BrBr
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc(C)c1Br
Yield: 94.7 %

Procedure:
Under an inert atmosphere, 225 g of acetic acid was put into a 500 ml three-necked flask, and 24.3 g of 5-t-butyl-m-xylene was added. Then, after adding 31.2 g of bromine, it was reacted at 15-20° C. for 3 hours. The reaction liquid was added to 500 ml of water, and the deposited precipitate was filtrated. It was washed with 250 ml of water twice and 34.2 g of white solid was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([OH:17])([CH3:16])[C:14]#[CH:15]>C(N(CC)CC)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]([OH:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCCCc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
1-Bromo-4-butylbenzene (235 g), 3-methyl-1-butyne-3-ol (139 g), triphenylphosphine (4.8 g) and bis(triphenylphosphine)palladium(II) chloride (2.8 g) were dissolved in triethylamine (1,000 ml), and then copper(I) iodide (0.8 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed with 10% hydrochloric acid twice, and further with water twice, and then chloroform was distilled off therefrom. The residue was purified using silica gel-chloroform column chromatography to give 3-methyl-1-(4'-butylphenyl)-1-butyne-3-ol (100 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][N:31]1C(=O)C2=CC=CC=C2C1=O.O.NN>>[NH2:31][CH2:30][CH2:29][CH2:28][N:10]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NCCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
[2-[(3-Nitro-2-pyridinyl)amino]phenyl]phenylmethanone is reacted with (a) sodium hydride in solvent followed by N-(3-bromopropyl)phthalimide. The product of (a) is reacted with alcholic hydrazine hydrate and acid to give the title compound.
Reaction SMILES: C[Al](C)C.[N:5]1([S:10]([CH:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH3:14])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=[O:30])[NH:18][S:15]([CH:13]([S:10]([N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:11])=[O:12])[CH3:14])(=[O:17])=[O:16])[N:22]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 0 °C

Procedure:
9 ml (0.018 mol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) in 150 ml of dichloromethane. When the evolution of gas has ceased, 3.6 g (0.018 mol) of methyl 4-methoxy-6-methyl-1,3,5-triazin-2-ylcarbamate in 30 ml of dichloromethane are added dropwise, and the resulting solution is refluxed for 24 hours. It is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off, and the water phase is extracted twice with dichloromethane. The organic phase is dried and evaporated. After the crude product has been triturated with diethyl ether, 2.9 g (47% of theory) of 3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea of melting point 136°-137° C. are obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([OH:29])([CH3:28])[CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=1>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:16]([C:21]([OH:29])([CH3:28])[CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=1
Reactant: CCCCCCCCCBr
Reactant: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(Cl)cc1C(C)(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.9 %

Procedure:
Sodium hydroxide powder (20 mg, 0.5 mmol) and n-nonyl bromide (122 mg, 0.59 mmol) were added to a solution of 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-1)] (100 mg, 0.40 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred for 17 hours at room temperature. Ice-water was added to the resultant mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography and dried under reduced pressure, to thereby yield 2-(5-chloro-2-(n-nonyloxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as a colorless oily product (81.7 mg, yield: 54.5%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(c3ccccn3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(N2CCN(c3ccccn3)CC2)c1
Yield: 89.4 %

Procedure:
A solution of (S)-{1-[3-(4-pyridin-2-ylpiperazin-1-yl)phenyl]ethyl}carbamic acid tert-butyl ester (4.1 g, 10.7 mmol) and hydrochloric acid (4N, 11 mL) in dioxane (40 mL) was stirred at 40° C. for 5 h. The reaction mixture was concentrated under vacuum, dissolved into water (50 mL), and washed with dichloromethane (2×50 mL). The aqueous layer was based with 5N NaOH and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (2×100 ml), dried over sodium sulfate and concentrated under vacuum to afford the title compound as an oil (2.70 g, 89% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[C:11]([C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])(=[O:13])[CH3:12].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:19][C:15]1[N:16]=[CH:17][O:18][C:14]=1[C:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([OH:13])[CH3:12]
Reactant: CC(=O)c1ocnc1C
Reactant: c1ccsc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(C)(O)c1cccs1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Thiophene (3.36 g) in dry tetrahydrofuran (20 ml) was stirred and cooled to -40° C. under a dry nitrogen atmosphere and n-butyllithium (2.5M solution in hexane, 16 ml) was added dropwise. The mixture was allowed to warm to -20° C. and then after 1 hour was cooled to -70° C. 5-Acetyl-4-methyloxazole (5 g) in dry tetrahydrofuran (15 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm the room temperature and was stirred for a further 2 hours. Aqueous sodium hydrogen carbonate was added and the mixture was extracted with diethylether. The material thus obtained was purified by flash chromatography to give the title compound. M.p. 84°-85° C.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (2.50 g) and [2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (alternative name: H-OEG-OEG-OH)(1.47 g) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature overnight and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystallised on standing. Yield 96% (3.1 g). LCMS: Theoretical mass: 874.2. Found: 874.49.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:7](=[NH:10])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[C:1]([C:5]1[N:6]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:10]/[C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])/[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1csc(=N)n1C[C@H]1CCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\scc(C(C)(C)C)n1C[C@H]1CCCO1

Procedure:
The product from Example 318A and 5-chloro-2-methoxy-benzoic acid were processed using the method described in Example 300 to afford the title compound. 1H NMR (300 MHz, CDCl3) −2.23 (m, 1H), 3.67-3.76 (m, 1H), 3.83-3.89 (m, 1H), 3.90 (s, 3H), 4.40 (dd, J=15.0, 7.5 Hz, 1H), 4.57-4.68 (m, 2H), 6.35 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.7, 2.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H). MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.97 g, Example 40a), 3-(benzyloxy)benzeneboronic acid (1.0 g, Example 93b), tetrakis(triphenylphosphine)palladium(0) (0.09 g), toluene (7.5 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 3.5 ml) with heating at 120° C. for 2 hours 30 minutes. After work up the residue was purified by column chromatography over silica eluting with methanol:dichloromethane (5:95) to give the title compound as a white solid (1.07 g).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.S(Cl)([Cl:16])=O>>[F:1][CH:2]([F:13])[C:3]1[C:7]([C:8]([Cl:16])=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1F
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F

Procedure:
9.1 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid and 75.5 ml of thionyl chloride are refluxed for 1.5 hours. After cooling down, the reaction mixture is evaporated under vacuum to yield 10 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil. GC-MS; observed m/z: Molecular ion: (M+)=212; fragments: (M+.-Cl)=177 and (M+.-F)=193.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][OH:5])[C@@H:2]1[CH2:6][OH:7].C(OCC)(=O)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:7][CH2:6][C@H:2]1[C@@H:3]([CH2:4][O:5][S:15]([CH3:14])(=[O:17])=[O:16])[O:1]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1O[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC[C@@H]1O[C@@H]1COS(C)(=O)=O
Reaction time: 4 h

Procedure:
To a mixture of 2.3 g of cis-oxirane-2,3-dimethanol and 200 ml of ethyl acetate was added 9.3 ml of triethylamine and then 4.3 ml of methanesulfonyl chloride under ice-cooling, followed by stirring at the same temperature for 4 hours. The reaction mixture was filtered through silica gel and washed with ethyl acetate. Thereafter, the filtrate was evaporated, to give 5.4 g of the title compound.