Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)=[CH:35][CH:34]=1.O1CCOCC1>O1CCCC1>[F:26][C:23]([F:24])([F:25])[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([N:8]([CH3:32])[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:40]([NH:39][C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)=[O:41])=[CH:3][CH:4]=3)[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)([OH:31])[C:27]([F:30])([F:28])[F:29]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CN(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN(c1ccc(NC(=O)Nc2ccncc2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 29.2 %

Procedure:
2-(4-((4-((4-Aminophenyl)(methyl)amino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.260 mmol, 120 mg) and phenyl pyridin-4-ylcarbamate (0.390 mmol, 84 mg) were combined in tetrahydrofuran (1 mL) and dioxane (1 mL) and heated to 100° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to give the title compound (44.2 mg). MS (ESI) m/z 582.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:31])([O:4][C:5]([NH:7][C@H:8]([C:28]([OH:30])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6])[CH3:3].[C:32](=O)([O-])O.[K+].IC.O>CN(C)C=O>[CH3:3][C:2]([CH3:31])([O:4][C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:32])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine (5.00 g, 11.7 mmol) in N,N-dimethylformamide (10 mL) was treated with potassium hydrogen carbonate (1.4 g, 14.1 mmol) and iodomethane (0.8 ml, 12.9 mmol). The reaction mixture was stirred at room temperature for 2 h. Then water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and chromatographed (10-40% ethyl acetate/hexanes) to give N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (4.20 g, 81%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].O1CCCC1>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:23][CH:24]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:46][CH:45]=[CH2:44])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCN1CCc2nc(CCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2C1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.20 g), potassium carbonate (0.082 g), allyl bromide (0.057 g) and tetrahydrofuran (2 ml) is stirred overnight at room temperature. To the mixture is added chloroform, and the mixture is washed, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-5-allyl-3-[2'-(t-butoxycarbonyl)biphenyl- 4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.128 g).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][O:18][CH3:19])[O:13][C@H:12]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([CH2:44][C:45](O)=[O:46])=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(N=C=NC2CCCCC2)CCCCC1.O.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][O:18][CH3:19])[O:13][C@H:12]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([CH2:44][C:45]([N:7]1[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:46])=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC(=O)O)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)C1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC(=O)N4CCC(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
4-Isopropylpiperidine (J. Am. Chem. Soc. 2592, 68, 1946) (105 mg, 0.64 mmol) was added to a stirred solution of 2-{9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}acetic acid (300 mg, 0.58 mmol) (preparation 51), N,N′-dicyclohexylcarbodiimide (150 mg, 0.64 mmol), 1H-1,2,3-benzotriazol-1-ol monohydrate (110 mg, 0.71 mmol) and N-ethyl-N-isopropyl-2-propanamine (190 mg, 1.47 mmol) in dichloromethane (15 ml). The reaction mixture was stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure, then the residue treated with ethyl acetate and the mixture filtered. The solid was washed with ethyl acetate and the combined ethyl acetate filtrates washed with saturated aqueous sodium hydrogen carbonate solution, brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give some pure and some impure material. The impure material was then re-purified by column chromatography on silica gel eluting with a solvent gradient of ethyl acetate increasing in polarity to ethyl acetate:methanol (95:5). The pure fractions from both columns were combined to give the title compound (285 mg) as a foam. MS: 629 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28])#[CH:20]>>[OH:29][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCCN(C)C1=O
Product: CN1CCCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1=O
Yield: 17 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A1) to give the titled compound as a white solid (20 mg, 17%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:7][C@@H:6]1[CH3:25])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>C(#N)C.O>[CH3:25][C@H:6]1[CH2:7][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:9][C@@H:10]([CH3:11])[N:5]1[C:3](=[O:4])[CH2:2][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH3:32]
Reactant: COc1ccccc1O
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1OCC(=O)N1[C@H](C)CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@@H]1C
Reaction time: 4 h

Procedure:
2-Chloro-1-((2S,6R)-2,6-dimethyl-4-(naphthalene-2-ylsulfonyl)piperazin-1-yl)ethanone (200 mg, 0.52 moles) was dissolved in 20 mL of acetonitrile. Dry K2CO3 (106 mg, 0.79 moles) was added to the reaction mixture under nitrogen atmosphere and allowed to stir for about ten minutes. 2-methoxyphenol (97 mg, 0.78 moles) was slowly added to the reaction at room temperature and allowed the reaction to continue for another 4 h. The reaction was monitored by TLC and after product formation was observed, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with bicarbonate followed by brine & then dried over sodium sulphate. The solvent was evaporated on reduced pressure to afford crude product which was purified by column chromatography to yield the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@:4]([CH:22]=[CH2:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH:5]OCC1C=CC=CC=1.[ClH:25]>>[ClH:25].[CH:22]([C@@:4]([C:3]([OH:24])=[O:2])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH2:5])=[CH2:23]
Reactant: C=C[C@@](Cc1ccc(O)cc1)(NOCc1ccccc1)C(=O)OC
Agent: Cl
Product: C=C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Reaction time: 2 h

Procedure:
A mixture consisting of 0.554 g of benzyloxy-α-vinyltyrosine methyl ester and 40 ml of 6 N aqueous hydrochloride acid was heated at reflux with rapid stirring for 2 hours. The reaction mixture was cooled, extracted three times with 5 ml of methylene chloride and treated with activated charcoal. Filtration and evaporation of solvent gave 0.355 g of α-vinyltyrosine hydrochloride as an amorphous solid. NMR (D2O) showed: 3.35 (2H,AB, JAB =15, γAB =22), 5.55 (1H,d, J=18), 5.70 (1H,d, J=12), 6.43 (1H, d of d, J=18,12), 7.27 (2H,AB, JAB =9, γAB =22). m/e 207 (P-36).
Reaction SMILES: [CH2:1]([O:8]C1C=CC=CC=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:23]1[CH:30]=[CH:29][C:26](C=O)=[CH:25][CH:24]=1)C(C)C>O1CCCC1>[C:23]1([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:30]=[CH:29][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.2 %

Procedure:
A Grignard reagent was prepared from 2-benzyloxy-bromobenzene (0.20 g), magnesium (0.026 g), a catalytic amount of iodine and tetrahydrofuran (1 mL). The obtained Grignard reagent was added to a solution of 4-isobutylbenzaldehyde (0.16 g) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) to give a diphenylmethanol compound (0.23 g). The obtained diphenylmethanol compound was dissolved in ethanol (3 mL) and concentrated hydrochloric acid (0.1 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/hexane=1/1) to give 2-(4-isobutylbenzyl)phenol (0.10 g).
Reaction SMILES: [CH2:1]([C:4]1([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8](=[O:11])[O:7][C:5]1=[O:6])[CH2:2][CH3:3].P([O-])([O-])([O-])=[O:16]>C1COCC1>[CH2:1]([C:4]([CH2:10][CH2:9][C:8]([OH:7])=[O:11])([CH2:12][CH2:13][CH3:14])[C:5]([OH:16])=[O:6])[CH2:2][CH3:3]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC1(CCC)CCC(=O)OC1=O
Solvent: C1CCOC1
Product: CCCC(CCC)(CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of BSA (300 mg, 5×10-4 mmole) in 20 ml of phosphate buffer was added the hapten, 2,2-dipropylglutaric anhydride as prepared in Example 5 (55 mg, 0.25 mmole in 200 ml THF) in 4μl portions over an hour. The resulting clear solution was stirred at 4° overnight, after which it was dialyzed in 7×2 liter of water adjusted to pH 8 with phosphate buffer, followed by one time with deionized water. The dialysis took 5 days. Lyophilization gave 320 mg of conjugate having a hapten number of 40 as estimated by the amino group precipitation method.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH2:18][CH:17]=[CH2:16])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.52 g, 38 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 30 mmol), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 ,g 38 mmol). The mixture was stirred at 95±5° C. for one hour, cooled to room temperature, and added to water (250 mL). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 mL). The concentrated ethereal extracts were combined with the filtrated solid, taken up in 20% aqueous ethanol (100 mL), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 mL) and petroleum ethers (30°-60°, 50 mL), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 mL).
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][CH2:15][CH2:16][Br:17]>>[BrH:17].[CH:1]1([C:7]2[S:11][C:10](=[NH:12])[N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCBr
Reactant: Nc1ncc(C2CCCCC2)s1
Product: Br
Product: COCCn1cc(C2CCCCC2)sc1=N

Procedure:
A mixture of Example 182B and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 241 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[C@H:16]3[CH2:17][N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:2]3[CH:3]=[N:4][C:5]([O:8][C@@H:9]4[C@H:16]5[CH2:17][N:12]([CH2:13][CH2:14][CH2:15]5)[CH2:11][CH2:10]4)=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cnc(O[C@H]2CCN3CCC[C@@H]2C3)nc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1cc2cc(-c3cnc(O[C@H]4CCN5CCC[C@@H]4C5)nc3)ccc2[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
5.19 g (17.4 mmol) of (4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane is dissolved in 200 ml toluene/EtOH 9:1. 5-Indolyl boronic acid (3.47 g, 21.6 mmol), Pd(PPh3)4 (1.04 g, 0.873 mmol) and a soln. of Na2CO3 (7.38 g, 69.6 mmol) in 35 ml H2O is added. The reaction mixture is stirred at 90° C. for 15 h. After cooling to rt the mixture is filtered over hyflo, the filtrate is extracted with water and brine. The aq. layers are reextracted with AcOEt and the combined organic layers are dried over Na2SO4, filtered and the filtrate is evaporated. The resulting crude product is purified by FC (255 g silica gel, eluent AcOEt/MeOH/Et3N 70:27:3) and recrystallization from EtOH to give 3.87 g (67%) (4S,5R)-4-[5-(1H-indol-5-yl)pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane. MS (ES+): m/e=335 (MH+), m.p. 195-199° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=NC=1)(=[O:4])=[O:3].[N:13]1C=CN=C[C:14]=1CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:14][N:13]=1)(=[O:3])=[O:4]
Reactant: OCc1cnccn1
Reactant: CS(=O)(=O)OCc1cncnc1
Product: CS(=O)(=O)OCc1cnccn1

Procedure:
Pyrazin-2-ylmethyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using pyrazin-2-ylmethanol instead of pyrimidin-5-ylmethanol. LCMS-ESI+ (m/z): [M+H]+ calc'd for C6H8N2O3S: 189.03; found: 189.01.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].CCN([CH:23]([CH3:25])[CH3:24])C(C)C.[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>O>[CH3:28][C:27]1[CH:2]=[C:3]([C:12]2[O:16][N:15]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=3[O:13][CH3:14])[N:1]=2)[CH:4]=[CH:5][C:26]=1[C:30]1[CH:11]=[CH:6][CH:7]=[CH:25][C:23]=1[CH3:24]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)c(OC)c1
Temperature: 150 °C

Procedure:
The title compound was prepared following procedure described for example 43, step 1 to give 2,2′-dimethylbiphenyl-4-carbonyl chloride (0.50 mmol) as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 47 (112.11 mg; 0.50 mmol) and DIEA (170.06 μL; 1 mmol) were added under argon. The mixture was heated in the microwave at 150° C. for 15 min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4Cl, NaHCO3 and NaCl sat. solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated, the crude product was suspended in ACN, filtrated, recristalized in EtOAC and dried under vacuo, affording the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.15-8.12 (m, 2H), 8.06 (dd, J=7.6, 1.5 Hz, 1H), 7.77-7.72 (m, 2H), 7.38-7.27 (m, 4H), 7.14-7.11 (m, 1H), 4 (s, 3H), 3.92 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H). LC/MS (Method A): 415.3 (M+H)+. HPLC (Method A) Rt 6 min (Purity: 98.1%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]([F:26])([F:25])C(OC)=O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:20]([F:26])[F:25])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1Br
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(F)F)ccc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a solution of methyl 2-bromo-5-hydroxybenzoate (5.63 mmol, 1.30 g) in DMF (8 mL) was added cesium carbonate (11.3 mmol, 3.67 g) and methyl chlorodifluoroacetate (6.75 mmol, 0.71 mL), and the reaction mixture stirred at 90° C. for 16 h. After cooling to rt and dilution with ethyl acetate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/EtOAc (9:1, v/v) as the eluent. The product was obtained as a light yellow oil (560 mg, 35%). GC-MS m/z: 280 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](OC)=[O:24]>O1CCCC1.CCCCCC>[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](=[O:24])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: COC(=O)C(OC)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)CC(=O)c1ccncc1
Temperature: -40 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetylpyridine (12 g) in dry tetrahydrofuran (500 ml), under nitrogen and at −60° C., was treated with a solution of lithium bis(trimethylsilyl)amide in hexane (200 ml, 1M). The mixture was allowed to warm to −40° C. then treated with methyl dimethoxyacetate (12 ml). After standing at room temperature for 16 hours the reaction mixture was evaporated and the residue was triturated with diethyl ether to give the title compound as a yellow solid (22 g).
Reaction SMILES: [OH:1][C:2]1[C:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:23]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Yield: 87.8 %

Procedure:
An ethyl acetate solution of 7.0 g of the so-obtained 2'-hydroxy-3,4',6'-trimethoxy-4-methoxymethoxy-3'-(3-methyl-2-butenyl)chalcone was added to an ethyl acetate solution of 1.0 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was strongly stirred and hydrogen was adsorbed. Then, the mixture was stirred overnight, the palladium/carbon was removed by using Celite and the solvent was removed by distillation. The residue was dissolved in diethyl ether and crystallization was effected by addition of hexane to obtain 6.2 g (yield= 92%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([B:8])=[CH:5][CH:4]=1.S1C=CC=C1C[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[S:7][C:6]([B:8])=[CH:5][CH:4]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: c1csc(CN2CCOCC2)c1
Reactant: [B]c1ccc(CO)s1
Product: [B]c1ccc(CN2CCOCC2)s1

Procedure:
(5-Morpholin-4-ylmethyl-thiophen-2-yl)-boron acid is prepared analogously to (5-hydroxymethyl-thiophen-2-yl)-boron acid (described in example (2ab)) starting from 4-thiophen-2-ylmethyl-morpholine (1.83 g; 10 mmol).
Reaction SMILES: [O:1]1C=C[N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17]CNCC2)=[CH:8]C=1.N[C@H:19]([C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])C)=[O:25])=[O:23])[CH2:20][OH:21].[C:31]1([C:37]2[O:41][C:40]([C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:44][CH:43]=3)=[N:39]N=2)C=CC=CC=1>>[C:24]([OH:26])(=[O:25])/[CH:22]=[CH:19]/[C:20]([OH:21])=[O:1].[NH2:3][CH2:2][CH2:6][C:11]1[C:10]2[C:9](=[CH:8][CH:30]=[C:27]([O:26][CH2:24][C:22]([N:51]3[CH2:50][CH2:49][N:48]([C:45]4[CH:44]=[CH:43][C:42]([C:40]5[O:41][CH:37]=[CH:31][N:39]=5)=[CH:47][CH:46]=4)[CH2:53][CH2:52]3)=[O:23])[CH:29]=2)[NH:12][CH:17]=1
Reactant: CC(C)(C)OC(=O)C(=O)[C@@H](N)CO
Reactant: c1coc(-c2ccc(N3CCNCC3)cc2)n1
Reactant: c1ccc(-c2nnc(-c3ccc(N4CCNCC4)cc3)o2)cc1
Product: NCCc1c[nH]c2ccc(OCC(=O)N3CCN(c4ccc(-c5ncco5)cc4)CC3)cc12
Product: O=C(O)/C=C/C(=O)O

Procedure:
Compound 6 is prepared from intermediate 6A (54 mg; 0.16 mmol) and SerBOC acid (53 mg; 0.16 mmol) according to the procedure described for the preparation of Example 1 from 1C.