Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:25]3[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:26]3[CH2:31][OH:32])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:37]1([CH3:46])[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:25]3[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:26]3[CH2:31][OH:32])=[CH:22][C:23]=2[C:40]2[CH:41]=[CH:42][C:37]([CH3:46])=[CH:38][CH:39]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(-c2cc(N3C[C@H](O)C[C@H]3CO)ncc2N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 150 mg (0.238 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide, 38.7 mg (0.284 mmol) 4-tolylboronic acid, 0.75 ml 2 N sodium carbonate solution, 5.3 mg (0.024 mmol) palladium acetate and 12 mg (0.048 mmol) triphenylphosphine in 1.5 ml 1,2-dimethoxyethane was stirred at 80° C. for 2 h. The reaction mixture was treated with 10 ml 2 N sodium carbonate solution and extracted with two 15-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. Flash chromatography gave 112 mg (79%) of the title compound as a yellow foam. MS m/e (%): 596 (M+H+, 100)
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH:8]=O)[CH2:2][CH3:3].C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH3:28][Si:29]([CH3:68])([CH3:67])[CH2:30][CH2:31][O:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][N:40]([CH2:53][C:54]1[N:55]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])[CH:56]=[CH:57][N:58]=1)[C:41]([C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH2:49][NH:48][CH2:47][CH2:46]2)=[O:42]>>[CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][N:48]1[CH2:47][CH2:46][C:45]2[C:50](=[CH:51][CH:52]=[C:43]([C:41]([N:40]([CH2:53][C:54]3[N:55]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])[CH:56]=[CH:57][N:58]=3)[CH2:39][C:35]3[N:34]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:67])([CH3:68])[CH3:28])[CH:38]=[CH:37][N:36]=3)=[O:42])[CH:44]=2)[CH2:49]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)CCCC=O
Reactant: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc2c(c1)CCNC2
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCCN(CCC)CCCCN1CCc2cc(C(=O)N(Cc3nccn3COCC[Si](C)(C)C)Cc3nccn3COCC[Si](C)(C)C)ccc2C1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that 4-(dipropylamino)butanal was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and the compound 13 was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][N:11]=1
Reactant: Cc1ccc(-c2nc3ccccc3s2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3s2)nc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
In 800 ml of dry carbon tetrachloride was dissolved 20 g (0.088 mol) of 2-(benzothiazol-2-yl)-5-methylpyridine, followed by the addition of 16.4 g (0.092 mol) of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. The mixture was heated at reflex for 10 hours, after which time it was allowed to cool down to room temperature. The precipitated succinimide was filtered off, the filtrate concentrated to 200 ml and the resulting crude crystals collected by filtration. Yield 24 g. Recrystallization from ligroine yielded 19 g of 2-(benzothiazol-2-yl)-5-bromomethylpyridine as colorless needles.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=CC=CC=1C=C.Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(=O)(O)(O)O>>[CH3:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccccc1
Reactant: ClCCc1ccccc1
Agent: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 90 parts of styrene, 217 parts of o-chlorostyrene and 83 parts of o-chloroethylbenzene is added to 722 parts of 94 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours, whilst stirring vigorously. The mixture is then stirred for a further 2 hours at 35° to 40° C and the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 31 parts of 1-methyl-3-phenylindan and 140 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OCCl)c1cc(Cl)cc(Cl)c1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.37 g of chloromethyl 3,5-dichlorobenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.31 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3,5-dichlorobenzoate (present compound (39)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][N:29]([CH3:28])[C:30]5=[O:34])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2C#N)CC1
Yield: 81.9 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 189 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (364 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].CCCN.O.O[N:56]1[C:60]2[CH:61]=CC=C[C:59]=2N=N1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:56][CH:60]([CH3:61])[CH3:59])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: On1nnc2ccccc21
Solvent: CCCN
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)NC(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.1 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (50 mg, 0.073 mmol) in THF (5 mL) was added 2-methylethylamine (12 μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) and lyophilized to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-isopropyl-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (8 mg, 15%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 8.11 (s, 1H) 6.59 (s, 1H), 6.19 (s, 0.2H), 5.95 (s, 0.8H), 4.97-4.89 (m, 2H), 4.10-4.03 (m, 1H), 3.75 (s, 3H), 3.73-3.69 (m, 1H), 3.64 (s, 2H), 3.59 (s, 3H), 3.57 (d, J=16.0 Hz, 3H), 3.47-3.35 (m, 1H), 3.23 (d, J=18.7 Hz, 1H), 3.09-3.02 (m, 1H), 2.22 (s, 3H), 1.27 (d, J=6.0 Hz, 2.4H), 1.23 (d, J=6.0 Hz, 0.6H), 1.14 (d, J=17.5 Hz, 6H); MS (ESI−) m/z 723 (M−H); HPLC >99% (AUC), tR 12.93 min.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.ClC1C=CC(N)=CC=1C(F)(F)F.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[S:44])=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:44]2)=[CH:38][C:37]=1[C:45]([F:46])([F:47])[F:48]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Chloro-3-(trifluoromethyl)aniline was converted to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884], isomeric purity of 95%, in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 2 h. After addition of 1 ml MeOH and 1 ml HTDNF the mixture was stirred for 30 min, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (18.0 g) was purified by flash chromatography (silicagel, hexane/MTBE 9:1) affording 14.0 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (S)-methoxycarbonyl-phenyl-methyl ester (11) in form of a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: C1=COCCC1
Reactant: O=C1CC[C@@H](CO)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC[C@@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (1.78 g, 0.0153 mol) and 3,4-dihydro-2H-pyran (2.62 g, 0.0312 mol, Alfa) in 40 mL of CH2Cl2 was added PPTS (0.391 g, 0.00156 mol, Aldrich) slowly. After stirring at rt overnight, the reaction mixture was quenched with 5 mL of water. The mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give pale yellow oil. The crude product was purified by a silica gel column chromatography (3:1 (v/v) petroleum ether/EtOAc) to afford the title compound as colorless oil (2.7 g, 88%).
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH2:10]>>[Br:8][C:7]1[C:2](=[O:10])[NH:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O
Reactant: Nc1ncc(Cl)cc1Br
Product: O=c1[nH]cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 2-amino-3-bromo-5-chloropyridine (100 g, 0.482 tool) in water (815 mL) and concentrated HC1 (130 mL) was added a solution of sodium nitrite (33.26 g, 0.482 tool) in water (272 mL). The resulting suspension was allowed to warm to room temperature and stir for 18 hours, at which point the solids were filtered, washed with carbon tetrachloride (2×50 mL), and dried in a vacuum oven (40° C.) to yield 75.1 g (74.8%) of gray-yellow so lid, m.p. 170°-173° C.: IR (mineral oil (Nujol (trademark ) ) 3111, 3041, 2947, 2850, 2722, 1814, 1696, 1663, 1643, 1585, 1527, 1462, 1377, 1302, 1234, 1171, 1153, 1123, 1106, 1040, 917, 896, 876, 839, 747, 726, 644, 635, 561, 539, 523, 410, 251, 235, 225, 220cm-1 ; 1H NMR (300 MHz, D6 -DMSO)δ 7.72 (d, 1H, J=2.2Hz) , 8.08 (d, 1H , J=2 . 2Hz ), 12.41 (br s, 1H); 13C NMR (DMSO) δ 110.88, 115.35, 134.08, 142.64, 157.56; exact mass calculated for C5H3NBrClO=206.9086. High resolution mass spec. 206.9093.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28](/[C:30](=[CH:15]/[C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:12]([O:19][CH3:20])[CH:13]=3)/[C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: COc1cc(C=O)ccc1OCCCCCCCCO
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCO
Yield: 99 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(8-hydroxyoctyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(8-hydroxyoctyl)oxy]-3-methoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 99% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Br[CH2:2][CH:3]1[O:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[CH2:4]1.[C:11]1([S-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:11]1([S:17][CH2:2][CH:3]2[O:9][CH:8]3[N:5]([C:6](=[O:10])[CH2:7]3)[CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [S-]c1ccccc1
Reactant: O=C1CC2OC(CBr)CN12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2OC(CSc3ccccc3)CN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(3RS, 5SR)-3-Bromomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (210 mg, 1.0 mmole) in dry dimethylformamide (2 ml) was added dropwise to a stirred solution of sodium thiophenolate (1.2 mmole) in dry DMF (5 ml). The solution was stirred at room temperature with exclusion of moisture for 16 hours and was then diluted with ethyl acetate (30 ml). The solution was washed three times with water, dried, and the solvent removed to give a colourless oil. The oil was chromatographed on silica gel (15 g) using ethyl acetate/petroleum ether to give the title compound as a colourless gum (205 mg, 87%). (Found : M+, 235.06551. C12H13NO2S requires 235.06669. νmax (CHCl3) 1785 (β-lactam C=O)cm-1 δ p.p.m. (CDCl3) 2.6 - 3.5 [complex, 5H, C(6)H2, C(2)H, CH2SPh[; 4.10 [dd, J 11.5Hz, J' 6Hz, 1H, C(2)H]; 4.52 [quin., J 6Hz, 1H, C(3)H]; 5.43 [d, J 2.5Hz, 1H, C(5)H]; 7.48 (5H, aromatic H). m/e : 235 (M+, 100%), 192 (30), 123 (71).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCOCc1ccnc(Cl)c1
Yield: 71 %

Procedure:
4.30 g of 2-chloro-4-pyridinemethanol, 20 ml of dimethoxymethane and 0.57 g of p-toluenesulfonic acid monohydrate were suspended in 200 ml of benzene. The suspension was passed through a Soxhlet extractor containing 25 g of 2 Å molecular sieves, and refluxed for 20 hours. After cooling, the reaction solution was washed with a saturated solution of sodium hydrogen carbonate and water, dried, and concentrated under reduced pressure. The residue was distilled to give 4.0 g (yield 71%) of 2-chloro-4-(methoxymethoxymethyl)pyridine.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](C3C(C(OCC)=O)=CC=CC=3)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH2:39][CH3:40])=[C:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=1)(=O)C.[OH-].[Na+].O.[C:48]([OH:51])(=[O:50])C>C(O)C>[C:41]([C:34]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:48]([OH:51])=[O:50])=[CH:19][CH:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:37]=[CH:36][C:35]=1[NH:38][CH2:39][CH3:40])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(=O)O
Reactant: CCNc1ccc(-c2cc(-c3ccc(-c4ccccc4C(=O)OCC)cc3)ccc2OCCCOC(C)=O)cc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCO)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
900 mg (1.74 mmol; 1 eq.) of ethyl 4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-ethylamino-[1,1′;3′,1″]terphenyl-4-benzoate are dissolved in 10 ml of absolute ethanol. 312 mg (7.8 mmol; 4.5 eq.) of sodium hydroxide and 4 ml of H2O are added at room temperature and the mixture is then heated to reflux. These conditions are maintained for about 1 hour 30 minutes. The reaction medium is concentrated to a small volume; H2O is added to the precipitate formed, and the mixture is then acidified with acetic acid to pH ˜4-5. This suspension is fluidized by adding H2O and stirred at room temperature for 1 hour. The resulting mixture is filtered through a sinter funnel, rinsed with H2O until the filtrate is neutral, and oven-dried. 694 mg of 3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are thus obtained in the form of a white powder (yield=89%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:57]([O:64][CH2:65][C:66](O)=[O:67])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>ClCCl>[CH2:57]([O:64][CH2:65][C:66]([NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:67])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)COCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (1.30 g, 3.7 mmol) in dichloromethane (60 mL) was added diisopropylethylamine (1.5 g), followed by 1-hydroxybenzotriazole monohydrate (1.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (2 mL). The resulting mixture was stirred for 15 minutes and then benzyloxyacetic acid (1.2 mL) was added. After stirring for 2 hours the reaction mixture was washed with 10% HCl, 1 N NaOH and water, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the final amide as a dark yellow oil. The oil was purified by column chromatography (dichloromethane:MeOH=98:2) providing 1.64 g of pure final compound as a white solid in 89% yield. 1H NMR (300 MHz, CDCl3) δ 9.12, 8.29, 7.72, 7.63-7.49, 7.35-7.33, 6.99, 4.65, 4.10, 4.05-3.83, 3.66-3.54, 3.33-3.29. MS (ES+) m/z 500.2 (M+1).