Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[F:3][C:4]([F:31])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18](=[N:26]O)[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1>C(O)C.O1CCCC1.[Ni]>[F:31][C:4]([F:3])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]([NH2:26])[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4cc(OC(F)(F)F)ccc4[nH]3)cccc21
Yield: 90.9 %

Procedure:
The procedure used in Example 6 is followed. In a 111 ml autoclave, dissolve 730 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 25 ml of ethanol and 25 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 122 ml. After filtration of the catalyst over Celite, the filtrate is concentrated under reduced pressure and then taken up in dichloromethane and dried over magnesium sulphate. In this way, we obtain 640 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)amine, in the form of a beige foam, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1]([CH2:5][NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])(=O)[CH:2]=C.Cl[C:13](OCC)=O>>[CH3:13][C:7]1([CH3:8])[N:6]=[C:5]([CH:1]=[CH2:2])[O:10][C:9]1=[O:11]
Reactant: C=CC(=O)CN[C@@H](C)C(=O)O
Reactant: CCOC(=O)Cl
Product: C=CC1=NC(C)(C)C(=O)O1
Temperature: -78 °C

Procedure:
2-Vinyl-4,4-Dimethylazlactone (VDM) was prepared from N-acryloylmethylalanine (S. M. Heilmann and H. K. Smith II, J. Appl. Polym. Sci., 24, 1551 (1979)) by the Taylor and Platt procedure (L. D. Taylor and T. E. Platt, J. Polym. Sci. Polym. Lett. Ed., 7, 597 (1969)) with ethyl chloroformate as the dehydrating agent. A modified workup procedure was used in which, instead of cooling the filtrate to crystallize the product, the filtrate was concentrated on a rotary evaporator, and the crude product was distilled just above room temperature at 0.5 Ton. Receiving flasks were cooled to −78° C. to collect the product. Typical distilled yields were approximately 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14](=[NH:18])OCC)[CH:11]=[CH:10][C:9]=1[C:19](=[O:28])[NH:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[NH3:32].CO>>[C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:19]([NH:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:28])=[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)[N:13]=1)(=[NH:32])[NH2:18]
Reactant: N
Reactant: CCOC(=N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Solvent: CO
Product: N=C(N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of the ethyl 6-(3-fluorophenethylamino)-5-(pyridin-3-ylmethylcarbamoyl)picolinimidate and NH3/MeOH (7N, 0.76 mL) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness to give 6-carbamimidoyl-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide. LC/MS (M+H+) m/z 394.1.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:30]4[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1c(F)cccc1F
Reaction time: 20 h
Yield: 41.4 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 2,6-difluorobenzene-sulphonyl chloride (0.62 g) in dichloromethane (22 ml), under nitrogen, and stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave an orange gum. Trituration with petroleum ether (b.p. 40-60° C.) yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzenesulphonamide as an off-white solid (0.29 g); m.p. 122-124° C., [α]D22.5 -22.1° (c=1.0, CH2Cl2).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:10]1[O:12][CH2:11]1>CN(C)C(=O)C>[N:1]1([CH2:10][CH2:11][OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CO1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CC(=O)N(C)C
Product: OCCn1cnc2ccccc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 118 g of benzimidazole, 48.5 g of ethylene oxide, and 400 g of N,N-dimethylacetamide was heated and stirred in an autoclave at 100° C. for 16 hours. The solvent was distilled off in vacuo, yielding crude 2-(1H-benzimidazol-1-yl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][CH2:21][CH2:22][N:23](C)[CH3:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:24])=[O:14]
Reactant: COCCN(C)C
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: COCCN(C)C(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-methoxyethyl)-N-methylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.42 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of (2-methoxy-ethyl)-dimethyl-amine LC/MS [7.84 min; 430 (M+1)]
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C:35](Cl)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:35]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:36])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cccc2ccccc12

Procedure:
150 mg (0.431 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 39a with 75 μl (0.495 mmol) of 1-naphthoyl chloride and 81 μl (0.578 mmol) of triethylamine. The title compound ##STR89## is obtained (208 mg, 97%) as oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.85, FD-MS: M+ =516, 518; IR: 3680, 3400, 1620 cm-1.
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:20][C:14]1[CH:19]=[CH:18][C:17]([C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCCCCCCC(=O)O1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added the previously made Oxacycloundecane-2,11-dione (20 g, 108.5 mmol), phenol (10.22 g, 108.5 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (72.34 g, 542 mmol) was added and the reaction stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collect by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 The solids that formed were removed by filtration and the parent solution was continued to be acidified until pH 2.5. The crude product precipitate was collected by filtration and was washed with 1×100 mL water. The crude product was dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 and the impurities that precipitated were filtered off. The parent solution was further acidified until pH 2. The crude product was collected by filtration and washed with 2×50 mL water. The product was recrystallized form acetone. The isolated product (1.2 g, 4%) was collected by filtration. Found: C, 69.00; H, 7.81%; C16H22O4 requires C, 69.04; H, 7.97% 1H NMR (d6-DMSO): δ 12.0, bs, 1H(COOH); δ 10.3, bs, 1H (aryl-hydroxyl); δ 7.8 d, 2H (aryl H's); δ 6.8, d, 2H, (aryl H's); δ 2.9, t, 2H(CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.5, multiplet, 4H(CH2's β to carbonyl & β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCc2c(c3ccccc3n2S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester in methylene chloride (50 mL) is treated with 0.982 g of sodium hydroxide and stirred and room temperature overnight. Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirred at room temperature overnight. The reaction mixture is diluted with water (250 mL) and extracted with methylene chloride. The organics are combined, washed with water then a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).
Reaction SMILES: S1(CCCC1)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O=[C:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[C:43]([CH3:44])=[CH:42][C:41]([O:45][CH3:46])=[C:40]([O:47][CH3:48])[C:39]=1[OH:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].C([BH3-])#N.[Na+].[Cl-].[Na+]>C1CCCCC1.CN(C)C=O>[OH:49][C:39]1[C:40]([O:47][CH3:48])=[C:41]([O:45][CH3:46])[CH:42]=[C:43]([CH3:44])[C:38]=1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)CCCCCC(=O)O)c(O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: C1CCCCC1
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Product: COc1cc(C)c(CCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a solvent mixture of dimethylformamide (10 ml) and sulfolane (10 ml) containing p-toluenesulfonic acid (100 mg) is added 7-oxo-16-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)hexadecanoic acid (1.75 g) and p-toluenesulfonyl hydrazide (930 mg) at 100° C. After 5 minutes, cyclohexane (10 ml) and sodium cyanoborohydride (1.0 g) are added. The reaction is conducted at 100° C. for 20 minutes. Then, at room temperature, a saturated aqueous solution of sodium chloride (100 ml) is added, followed by extraction with ether (50 ml×2). The ether layers are combined, washed with water, 1N--HCl and water in that order, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is dissolved in chloroform and subjected to column chromatography on silica gel, elution being carried out with chloroform. The fractions containing the desired compound are pooled and the solvent is distilled off. To the crystalline residue is added petroleum ether and, after cooling, the crystals are collected by filtration. The above procedure yields 970 mg of 16-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)hexadecanoic acid, m.p. 45° C.-46° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[O:5][CH:6]=1.S(Cl)([Cl:14])=O>ClC(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([Cl:14])=[O:11])[O:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cc(Br)co1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)/C=C/c1cc(Br)co1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (E)-3-(4-bromofuran-2-yl)acrylic acid (3.8 g, 17.51 mmol) in 35 mL of trichloromethane was added a solution of 2.6 mL of thionyl chloride in 200 μL of DMF. The reaction mixture was refluxed for 1 h and after cooling to room temperature concentrated to give 4 g (97% yield) of the title compound as light brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([F:31])=[C:23]([F:22])[CH:24]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1F
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)c(F)c2)cc1
Yield: 57.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3,4-difluoro-benzyl bromide (145 mg, 0.6 mmol) to afford the title product, (120 mg, 55% yield); LCMS, 100% APCI+, Calcd; 419.5. Found m/z: 421.4 (M+2). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 4.95 (s, 2H), 6.84-6.88 (m, 4H), 7.55-7.28 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[N:26]=[C:27]=[O:28].C(OCC)(=O)C>O1CCOCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[NH:26][C:27]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:17])[CH3:1])[CH:4]=2)[N:11]=[CH:12][N:13]=1)=[O:28]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2cc(NC(=O)Nc3c(F)cccc3F)ncn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine (458.6 mg, 2 mmol), 2,6-difluorophenyl isocyanate (341.2 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 2.5 h at 80° C. After cooling down, the reaction mixture is treated with ethyl acetate. The precipitate is filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>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>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 76.3 %

Procedure:
A flask containing 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.300 g, 0.634 mmol), phenylboronic acid (0.0696 g, 0.570 mmol), a 2.00 M solution of K2CO3 in H2O (0.317 mL), EtOH (0.0944 mL) and toluene (1.417 mL) was purged with argon for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.0264 g, 0.0229 mmol) was added and the mixture was refluxed overnight. The reaction was cooled and diluted with H2O. The aqueous layer was extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to afford the title compound (0.224 g, 76%).
Reaction SMILES: OC1C([NH2:11])=CC=CC=1C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH2:11]
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C=Nc1ccccc1Br
Product: NC(=O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 3-amino benzoic acid (300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane (0.287 g, 41%). EI-MS m/z 351 (M+H)+
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:31]([O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:33])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and ethyl carbonochloridate (38 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then solvent was evaporated. EtOAc was added, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(ethoxycarbonylamino)-2-phenylacetate (60 mg; 55% yield). The product was used as such in the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH:2]=[CH2:3].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][C:13]([OH:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCC1=C(CC(=O)OCc2ccccc2)C(C)(C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCC1=C(CC(=O)O)C(C)(C)CCC1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a solution of benzyl 2-(2-allyl-6,6-dimethyl-cyclohexen-1-yl)acetate (1.5 g, 5.02 mmol) in dioxane (12 mL) and water (4 mL) was added NaOH (2M, 5.5 mL). The solution was heated to 100° C. for 30 h. The solution was concentrated in vacuo and water was added. The aqueous layer was extracted 2 times with ether and the organic layer was removed. Then, pH of the aqueous layer was adjusted to 1. The solution was extracted with ethyl acetate and washed with brine, dried and concentrated to give the desired product as a colourless oil (1.05 g, quant). 1H NMR (400 MHz, CDCl3) δ 5.77 (1H, dd, J=16.9, 10.3 Hz), 4.88-5.09 (2H, m), 3.13 (2H, s), 2.74 (2H, d, J=6.2 Hz), 1.96-2.08 (2H, m), 1.59-1.69, (2H, m), 1.43-1.57 (2H, m), 0.98-1.06 (6H, s) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=O)(C)(C)C.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:71][S:72][C:73]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)([C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH:69]=O)=[O:66])([CH3:63])([CH3:62])[CH3:61]>ClCCl.ClC(Cl)C>[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:71][S:72][C:73]([C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:69][N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: CCCOCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C

Procedure:
The product of Step B (0.330 g, 0.772 mmol) was first treated with trifluoroacetic acid (10 mL) in dichloromethane (10 mL); the crude trifluoroacetate salt was then reacted with sodium triacetoxyborohydride (0.653 g, 3.09 mmol), 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropanal (0.415 g, 0.927 mmol) in dichloroethane (15 mL) in the presence of crashed molecular sieves following the procedure described in Example 1, Step D. The title compound was obtained as a gum (0.572 g).