Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([OH:30])[CH3:29])[C:12]1=[O:31])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=1)=[O:43].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:32]([CH:10]([CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([O:30][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])[CH3:29])[C:12]1=[O:31])[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(COC(=O)CC2C(C(C)O)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)CC2C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
2.6 g of 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone was dissolved in 15 ml of dried methylene chloride, and 1.22 g of 4-dimethylaminopyridine was added thereto. Under ice-cooling, a solution of 1.3 g of p-nitrobenzyl chloroformate in 7 ml of dried methylene chloride was added dropwise to the mixture, followed by stirring at room temperature for 1 hour. To the reaction mixture were added methylene chloride and water, and the methylene chloride layer was washed successively with a 1N hydrochloric acid aqueous solution, water, a 5% aqueous solution of sodium bicarbonate and water, and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel chromatography to obtain 2.2 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12.[OH-].[Na+].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37]>O.CCOCC>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([NH:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12)=[O:37]
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)n2nc(CO)nc2n1
Yield: 80.2 %

Procedure:
In 100 ml of water was suspended 4.6 g of 7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin7-yl)thiomethyl]-3-cephem-4-carboxylic acid obtained in Example 2, and a 2N aqueous sodium hydroxide solution was added to the suspension and the mixture was dissolved at a pH 7. To this solution was while stirring under ice-cooling added dropwise a solution of 1.93 g of 2-thienyl acetyl chloride in 20 ml of ether over one hour. During this time, a pH of the mixture was maintained to 7 to 7.5 by addition of a 2N aqueous sodium hydroxide. After stirring for further one hour, the reaction mixture was washed with ethyl acetate. The reaction mixture was adjusted to pH 2.5 with a 2N hydrochloric acid under ice-cooling and stirring, and precipitated crystals were collected by filtration, washed with water and dried to obtain 4.81 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:17]O)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16].[BrH:19].[C:20]([OH:23])(=O)[CH3:21].C(=O)(O)[O-].[Na+]>O.ClCCl.CC(C)=O>[C:20]([O:1][CH:2]([CH2:17][Br:19])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16])(=[O:23])[CH3:21]
Reactant: CC(=O)O
Reactant: Br
Reactant: Cc1cn(C)c(=O)n(CCCCC(O)CO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)OC(CBr)CCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 3-(5,6-dihydroxyhexyl)-1-methylthymine (1.65 g, 6.4 mmol) and a 30% solution of hydrogen bromide in acetic acid (3.8 mL, 19.3 mmol) in water (5 mL) and acetone (10 mL) was stirred for 1.5 hours. The mixture was then added to a flask containing sodium bicarbonate (6.7 g), water (40 mL) and dichloromethane (50 mL). After 15 minutes of vigorous stirring, the layers were separated and the aqueous layer washed with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate. The solvent was evaporated under vacuum to yield 2.30 g (100%) of 3-(5-acetoxy-6-bromohexyl)-1-methylthymine as a yellow oil. The bromoacetate was used in the next step without further purification. A solution of 3-(5-acetoxy-6-bromohexyl)-1-methylthymine (2.30 g, 6.4 mmol) in methanol (10 mL) was treated with a 1 M methanol solution of sodium methoxide (7 mL). After stirring for 15 minutes, the solution was poured into water (60 mL) and extracted with 20% ethanol/dichloromethane (2×70 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated under vacuum to yield 1.30 g (85%) 3-(5,6-oxidohexyl)-1-methylthymine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1)[CH2:18][CH3:19]>>[CH2:17]([N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1)[CH2:18][CH3:19]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
177 mg of compound 4 was obtained in a similar manner to those described in the Example 1 and 2 using 481 mg of ethyl 4-(2-aminophenoxy)butyrate and 262 mg of 3-(1-propylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CC(C)=O>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH3:1][N+:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1
Reactant: CN1CCCC(O)C1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: C[N+]1(C)CCCC(O)C1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 164.1 %

Procedure:
In 20 ml of acetone was dissolved 2.30 g of 1-methyl-3-piperidinol, and 3.72 g of methyl p-toluenesulfonate was added dropwise to the resulting solution. The mixture was stirred at room temperature, heated under reflux, and cooled to precipitate crystals. The crystals were collected by filtration and dried to give 4.94 g of the desired product, m.p. 125°-127° C. (decomp.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[F:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:1]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=3)[C:6]([OH:8])=[O:7])=[N:20][C:15]=2[CH:14]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: CCO
Product: O=C(O)c1cccc(-c2nc3cc(F)ccc3[nH]2)c1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 3-formylbenzoic acid (500 mg, 3.33 mmol) and 4-fluorobenzene-1,2-diamine (420 mg, 3.33 mmol) in ethanol (10 mL) was refluxed for 5 hours. After cooling to room temperature, the precipitate was collected by filtration and dried to give 311 mg (36%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:31]([NH:30][C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=2[Cl:19])=[O:32])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 2-chloro-4-trifluoromethyl-phenyl isocyanate (0.107 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 57 as a colorless solid (0.085 g, 40%). LCMS m/z (%)=489 M+H+ (37Cl, 25), 488 M+H+ (35Cl37Cl, 25), 487 M+H+ (35Cl, 100), 1H NMR (400 MHz, acetone-d6) δ: 8.88 (bs, 1H), 8.544 (bs, 1H), 8.063 (s, 1H), 7.669 (d, J=1.54 Hz, 1H), 7.606 (d, J=2.69 Hz, 1H), 7.58 (t, 1H), 7.549 (d, J=1.51 Hz, 1H), 7.385 (d, J=2.68 Hz, 1H), 7.68-7.64 (m, 1H), 7.080 (d, J=8.98 Hz, 1H), 4.145 (m, 1H), 3.742 (s, 3H), 1.345 (d, J=6.61 Hz, 3H), 1.188 (d, J=6.61 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[S:17][CH:18]=1.N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[C:19]([C:16]1[S:17][CH:18]=[C:14]([CH3:13])[N:15]=1)[C:20](=[O:23])[CH2:21][CH3:22])[C:7]#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CCC(=O)Cc1nc(C)cs1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1

Procedure:
400 mg (2.48 mmol) of the compound from example 3A and 924 mg (2.73 mmol, 50% purity) of the compound from example 5A are dissolved in 10 ml of dichloromethane, and 0.245 ml (2.48 mmol) of piperidine and 0.142 ml (2.48 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 657 mg (83% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3([C:22](=[O:47])[NH:23][C@@H:24]([C:26]4[C:31]([F:32])=[CH:30][C:29]([C:33]5[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=5[C:41]5[N:45]=[C:44]([CH3:46])[O:43][N:42]=5)=[CH:28][N:27]=4)[CH3:25])[CH2:21][O:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:29]2[CH:30]=[C:31]([F:32])[C:26]([C@H:24]([NH:23][C:22]([C:18]3([NH2:17])[CH2:21][O:20][CH2:19]3)=[O:47])[CH3:25])=[N:27][CH:28]=2)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)NC(=O)C3(NC(=O)OCC4c5ccccc5-c5ccccc54)COC3)c(F)c2)no1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)NC(=O)C3(N)COC3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester (71.9 mg, 0.107 mmol, step C) in DCM (5 ml) was added piperidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The colorless solution was concentrated to dryness under high vacuum. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 98:2-95:5) and the title compound was obtained as colorless gum (36 mg, 75%). MS: 450.2 [M+H]+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19](=S)[NH2:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.C([O-])(=O)C.[NH4+:28].C([O-])(=O)C>ClCCl>[C:19]([C:12]1[S:11][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[N:14][C:13]=1[C:15]([F:18])([F:17])[F:16])(=[NH:20])[NH2:28]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=S)s1
Agent: CC(=O)[O-]
Solvent: CI
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(=N)N)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-4-trifluoromethylthiazole-5-thioamide [sic] (2.5 g, 7.32 mmol) was dissolved in dichloromethane (10 ml), and iodomethane (10.4 g, 73.24 mmol) was added. Then, the mixture was stirred for 48 hours at room temperature. After the solvent had been removed on a rotary evaporator, the residue was taken up in methanol (5 ml), and 10% strength methanolic ammonium acetate solution (8.5 ml, 10.98 mmol) was added. After the mixture had been stirred for 4 days at room temperature, the solution of the crude product was passed over an acetate-loaded ion exchanger and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography. Yield: 0.8 g (2.08 mmol, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C=C(O[C:21](OC2N=CC=CC=2)=[S:22])N=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]=[C:21]=[S:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: ClCCl
Product: COC(=O)c1cc(N=C=S)ccc1OC
Reaction time: 0.5 h

Procedure:
According to the method of Tet. Let., 26, 1661 (1985), combine methyl 2-methoxy-5-aminobenzoate (0.5 g, 2.76 mmol) and di-2-pyridyl thionocarbonate (0.64 g, 2.76 mmol) in dichloromethane (10 mL). After 30 minutes, dilute the reaction mixture with dichloromethane and extract five times with water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-thioisocyanatobenzoate: Rf=0.51 (silica gel, dichloromethane).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].N1C=CN=C1>CN(C=O)C.O>[CH:1]([Si:4]([O:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Br:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1ccccc1Br)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Triisopropylsilyl chloride (8.0 ml, 46.0 mmol) was added dropwise to a solution of 2-bromobenzyl alcohol (7.0 g, 39.6 mmol) and imidazole (5.1 g, 75.0 mmol) in DMF (25 ml) and the resulting solution stirred at 20° C for 18 hours. The reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts was washed with saturated brine (1×75 ml), dried (MgSO4) and concentrated to yield the title compound as a clear oil (10.2 g, 78%). 1H NMR (250 MHz, CDCl3) δ 1.05-1.24 (21 H, m), 4.82 (2 H, s), 7.11 (1 H, dt, J=7.5, 1.2), 7.34 (1 H, t, J=7.6), 7.48 (1 H, dd, J=7.9, 1.1), 7.63 (1 H, d, J=6.7).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][OH:10].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([O:10][CH2:9][CH2:8][CH:7]([CH3:6])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: CC(CCO)CCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CCOC(=O)CCl)CCc1ccccc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A 127.05 g (1.125 mol) of chloroacetyl chloride and 200 ml of dichloromethane were put into a flask and, while stirring under ice-cooling, a mixture consisting of 199.6 g (1.12 mol) of 3-methyl-5-phenylpentanol and 88.59 g (1.12 mol) of pyridine was added dropwise thereto spending 2 hours (reaction temperature 5 to 15° C.). After completion of the dropwise addition, this was further stirred at room temperature for 3 hours, and white crystals of the thus precipitated pyridine hydrochloride were removed by filtration. The reaction mixture was washed with water (3×300 ml), the organic phase was dehydrated with anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. By distilling the remained yellow oil under a reduced pressure, the title compound was obtained as a light yellow transparent oil. Yield 242.25 g (0.849 mol; yield 84.9%, boiling point 148-151° C./0.2 kPa).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1B(O)O>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Yield: 77.9 %

Procedure:
Bis(tricyclohexylphosphine)palladium (200 mg, 0.3 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (3.68 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and 2,4,5-trifluorophenylboronic acid (3.5 g, 20 mmol) in 100 mL dioxane and 10 mL H2O were reacted as above and purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to give 2.9 g (77.9%) of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:36]>CN(C)C=O.O.Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:36])[CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate (46.1 g) in N,N-dimethylformamide (200 mL) was added to a slurry of sodium hydride (2.83 g) in N,N-dimethylformamide (300 mL) at 5° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 5° C., then was treated with iodomethane (16.6 g), allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was then poured into ice/water (400 mL), diluted with water (250 mL) and 1N hydrochloric acid (250 mL). The resulting aqueous solution was extracted with ethyl acetate. The combined organic extract was washed (1N hydrochloric acid, water, brine), dried (MgSO4), filtered and evaporated. The residue was triturated with warm diethyl ether and filtered to give methyl 4-(5-benzyloxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (42.4 g, 89%); partial NMR (300 MHz, CDCl3): 3.75 (s, 3H, NCH3), 3.87 (s, 3H, CO2CH3), 3.90 (s, 3H, OCH3), 4.12 (s, 2H, CH2), 5.36 (s, 2H, OCH2), 6.82 (s, 1H, indole-H(2)), 8.38 (d, 1H, indole-H(4)).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reaction time: 2 h

Procedure:
A solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.03 g, 3.75 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in methylene chloride (15 mL) is cooled to 0° C., then MeSO2Cl is added dropwise. After 2 hrs, TLC indicated that the reaction is not complete, 10 mol % more of triethyl amine and MeSO2Cl are added. After additional 2 hrs, the reaction mixture is diluted with methylene chloride and washed with sodium bicarbonate, water and brine, dried over sodium sulfate. Concentration gave the crude title compound, which is used for the next step without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([Br:7])[N:6]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:22][CH:23]([CH3:25])[CH3:24])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18]2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1sc(Br)nc1Br
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Temperature: 25 °C

Procedure:
2,4-dibromo-5-methyl-thiazole (1.189 g, 3.563 mmol), (S)—N-Boc-2-isobutylpiperazine (863.5 mg, 3.563 mmol) and potassium carbonate (1.477 g, 10.69 mmol) in DMF (15 mL) were heated at 95° C. for 18 h. Cooled to rt, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity); 1H NMR DMSO-d6 δ 0.90 (t, 6H), 1.36-1.31 (br m, 2H), 1.42 (s, 9H), 1.46-1.42 (masked signal, 1H), 2.18 (s, 3H), 3.02-2.91 (m, 2H), 3.14 (dd, 1H), 3.60 (d, 1H), 3.78-3.68 (m, 1H), 3.86 (d, 1H), 4.19 (br s, 1H); ES+ 420.11.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)CO>O>[CH3:28][C:26]1[CH:25]=[CH:24][C:15]2[O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[CH2:13][C:14]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(C)ccc1O2

Procedure:
22.0 G. of 4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester and 22 g. of potassium hydroxide are stirred in 320 ml. of ethyleneglycol and 1.5 ml. of water for 90 minutes at 160° C. After cooling, the mixture is diluted with 1.3 liters of water and extracted three times with ether. The ethereal extracts are washed twice with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo, and there is obtained crude 1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-piperazine as an oil.