Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.400 g, 1.448 mmol) in dry dichloromethane (17.66 mL) was added triethylamine (0.504 ml, 3.62 mmol), 2-chloro-1-methylpyridinium iodide (0.433 g, 1.694 mmol), and 2-amino-5-bromopyridine (0.311 g, 1.795 mmol) sequentially at room temperature under nitrogen. The reaction mixture was heated to 50° C. for 1 hour then purified on the mass directed HPLC (30×100 mm Waters Sunfire column; 5 micron; 50 ml/min; acetonitrile/water with 0.1% TFA over 15 min). Fractions containing the title compound were concentrated under vacuum then lyophilized overnight to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: NCCCO
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 3-amino-1-propanol (0.27 ml; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 1 hour at room temperature. It is washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (230 mg; 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O)#[N:2].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:32]=[CH:31][CH:30]=2)[C:1]#[N:2])[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C#N)c3)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C#N)c4)n3n2)cc(OC)c1OC

Procedure:
In a similar manner as described for Example 1,3-cyano-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 17) (0.12 g, 0.25 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}benzonitrile (0.023 g) as a yellow solid. 1H NMR (CDCl3): δ8.84 (s, 1H), 8.79 (d, J=8.1 Hz, 1H), 8.74 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.54 (dd, J=7.9, 7.8 Hz, 1H) 7.09 (s, 1H), 6.83 (s, 2H), 3.85 (s, 3H), 3.81 (s, 6H), 2.60 (s, 3H). MS m/z 417 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:9][N:8]=[C:7]([S:20][CH3:21])[N:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl.O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[O:2][C:3](=[O:4])[C:5]2[N:6]=[C:7]([S:20][CH3:21])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc(SC)ncc1C#Cc1ccccc1Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2cc(-c3ccccc3Cl)oc(=O)c2n1
Yield: 110 %

Procedure:
A mixture of 5-(2-chloro-phenylethynyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (5.0 g, 9.4 mmol) (prepared in a manner similar to that described above), 50% (v/v) trifluoroacetic acid in dichloromethane (15 ml) and water (1 ml) was stirred in a heavy-walled Smith process vial and irradiated to 120° C. for 45 min. The mixture was evaporated in vacuo to dryness and the residual oil was purified by flash column chromatography over silica using a 3:7 mixture of hexane and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 6-(2-chlorophenyl)-2-methylsulfanylpyrano[3,4-d]pyrimidin-8-one (3.15 g) as a pale yellow oil. 250 MHz 1H-nmr (CDCl3) δ (ppm): 2.65 (s, 3H) (—SCH3), 6.95 (s, 1H) (═CHAr), 7.25-7.4 (m, 3H) (ArH), 7.65 (m, 1H) (ArH), 8.85 (s, 1H) (ArH); m/z (M+H)+. 305, HPLC purity 100%, HPLC retention time 3.66 min.
Reaction SMILES: [K].[CH2:2]([O:9][C:10]1[CH:15]=[C:14](Br)[CH:13]=[C:12]([F:17])[C:11]=1[N:18]1[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([CH3:26])[CH:13]=[C:12]([F:17])[C:11]=1[N:18]1[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CN(c2c(F)cc(Br)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(F)c(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 120 °C

Procedure:
To a microwave vial is added 150 mg (0.33 mmol) of 5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt and 125 mg of polystyrene-tetrakis(triphenylphosphine)palladium(0) (0.1 mmol/g) followed by 4.5 mL DME. To this is added 80 mg (1.33 mmole) of methylboronic acid followed by 1.3 mL of a 2.0 M aqueous solution of sodium carbonate. The mixture is heated in a microwave apparatus at 120° C. for 30 min. The resin is filtered and the solvent is removed under reduced pressure. Water is added to the residue and the solution is washed with MTBE. The aqueous phase is used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:26]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[CH3:27]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:29]5[C@H:28]([CH2:26][CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 67.2 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (292 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N)cc1
Yield: 94.5 %

Procedure:
(E)-Ethyl 3-(4-nitrophenyl)acrylate (11.7 g, 52.9 mmol) in tetrahydrofuran (100 ml) was hydrogenated over 10% Palladium-Carbon (1.20 g) at atmospheric pressure. After removal of the catalyst, the filtrate was concentrated in vacuo to give ethyl 3-(4-aminophenyl)propionate as a yellow oil (9.66 g, 95%).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>C1COCC1>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:18]2([OH:26])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2(O)Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF(250 mL) was stirred at room temperature for 2 hours under nitrogen. 4-t-Butylphenylmagnesium bromide (70.0 mL of 2.0 M solution in diethyl ether, 140.0 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. 2-Indanone (1.34 g) was distilled off at 80° C./0.3 mm Hg. The residue was washed with pentane (50 mL) and subject to Kugelrohr distillation(185° C./0.3 mm Hg). 2-(4-t-Butyl-phenyl)-2-indanol (23.43 g) was obtained in pure form. 1H-N.M.R. (CDCl3) d 1.32 (s, 9H), d 1.36 (s, 1H), d 3.25 (d, J=16.2 Hz, 2H), d 3.50 (d, J=16.2 Hz, 2H), d 7.15-7.45 (m, 8H)
Reaction SMILES: C([Li])CCC.C(O[CH:9]([O:15]CC)[N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)C.[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1C(N1CCCC1)=O.[Cl-].[NH4+]>O1CCCC1.CO>[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:9]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[O:15]
Reactant: CCOC(OCC)n1ccnn1
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1OCc1ccccc1C(=O)n1ccnn1
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
At −20° C., 2.8 g (0.01 mol) of 23% pure n-butyllithium are added dropwise within 15 minutes to a solution of 1.7 g (0.01 mol) of N-diethoxymethyltriazole in 10 ml of tetrahydrofuran. Stirring is continued for 15 minutes at −20° C., and 1.48 g (0.005 mol) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine dissolved in 10 ml of tetrahydrofuran are then added, and the mixture is stirred for a further 30 minutes at −20° C. 2 g of ammonium chloride and 10 ml of methanol are added and the mixture is heated under reflux for 15 minutes. The volatile components are removed under reduced pressure, the residue is admixed with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes when treated with a mixture of diethyl ether and petroleum ether in the ratio of 1:1. 0.5 g (17% of theory) of 3-[2-(2-methylphenoxymethyl)-benzoyl]-triazole of melting point 179° C. is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:31])[N:12]([CH:19]1[CH2:24][CH:23]([O:25]C(=O)C)[C:22](=[O:29])[NH:21][C:20]1=[O:30])[C:13]2=[O:18])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:31])[N:12]([CH:19]1[CH2:24][CH:23]([OH:25])[C:22](=[O:29])[NH:21][C:20]1=[O:30])[C:13]2=[O:18])=[O:7]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(NC(=O)c4ccco4)c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(Nc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O)c1ccco1

Procedure:
A solution of 3-[4-(2-furylcarbonylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine (1.33 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (20 mL) is heated at reflux for 5 hours. The solvent is removed in vacuo to give 3-[4-(2-furylcarbonylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-hydroxypiperidine which is further purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>ClCCl>[CH2:24]([O:23][C:21]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)/[C:7]1=[O:11])=[O:22])[CH3:25]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\c2ccc(Cl)cc2)c2ccc(Cl)cc21
Yield: 73.3 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (3.3 g, 11.3 mmol) was reacted with ethyl chloroformate (1.62 mL, 17.0 mmol) and triethylamine (3.16 mL, 22.6 mmol) in dichloromethane to give E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 3.0 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH2:30][CH3:31])[C:21]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]#[C:26][CH3:27])=[O:22].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:20]([CH2:30][CH3:31])[C:21]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]#[C:26][CH3:27])=[O:22])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Cl)cc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncc(Cl)cc2c1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a stirred mixture of 3-chloro-6-hydroxyquinoline (0.130 g) and anhydrous potassium carbonate (0.110 g) in dry N,N-dimethylformamide (3 ml) at 80° C. was added 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.197 g) and the reaction maintained at this temperature for 6 hours. The brown suspension produced was cooled to ambient temperature, poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; hexane/ethyl acetate 4:1 by volume) to give 2-(3-chloro-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (0.167 g) as a colourless solid, m.p. 105–107° C., 1H NMR (CDCl3) δ: 1.08(3H, t); 1.58 (3H, s); 1.59(3H, s); 1.77(3H, s); 1.99–2.08(2H, m); 4.55(1H, t); 6.37(1H, s); 7.02(1H, d); 7.41(1H, dd); 8.01(1H, d); 8.02(1H, d); 8.70(1H, m); 8.78(1H,m).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(C(C)=O)C>[CH2:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[N:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[N:13][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(O)cn2)C(O)C1
Reactant: BrCCCOCc1ccccc1
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(O)C1
Temperature: 80 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of 65 mg (0.22 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(5-hydroxy-pyrimidin-2-yl)-piperidine-1-carboxylate and 151.2 mg (0.66 mmol) of (3-bromo-propoxymethyl)-benzene in 10 ml of methyl ethyl ketone was stirred at 80° C. for 48 hours under argon. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene chloride and the solution was chromatographed directly on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 40 mg (41% of theory) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-hydroxy-piperidine-1-carboxylate as a foam; Rf : 0.43 (silica gel; methylene chloride:ethyl acetate=1:4 v/v).
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[N:17]1([CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: c1ccc(COc2ccc(OCCCN3CCCCC3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(OCCCN2CCCCC2)cc1
Temperature: 68 °C

Procedure:
A suspension of the product of Example 6 (2.5 g), ammonium formate (2.7 g), and 10% palladium on carbon (2.5 g) in methanol (100 mL) was heated in a 68° C. bath for 3 h, and allowed to cool to room temperature. The mixture was filtered through Celite, and the filtrate was evaporated in vacuo. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane (4×30 mL). The combined organic phases were dried (magnesium sulfate) and evaporated in vacuo, yielding the title compound as a pink microcrystalline solid (1.3 g) which was used without further purification. A small sample (100 mg) was recrystallized (ethanol) to obtain the title compound as beige prisms (68 mg).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>CCCCCCC>[C:5]12([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=3[O:21][CH3:20])[C:26]([O:28][CH3:29])=[O:27])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, under a nitrogen environment, are placed 2 g of 1-acetoxyadamantane and 20 ml of n-heptane. After total dissolution, 0.5 g of concentrated sulfuric acid is added drop by drop. At a temperature of approximately 20.C, 1.71 g of methyl 4-methoxybenzoate is added slowly and agitated for 48 hours. The solid obtained is filtered with sintered glass and washed with water until neutrality is reached. After drying in a vacuum oven for 24 hours at 25 C, one recovered 2 g of expected raw product (Melting point: 136°-137° C.).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:11]=2[F:31])=[CH:8][CH:7]=[N:6][CH:5]=1.CO.O.[OH-].[Li+]>O1CCCC1>[C:27]([O:26][C:24]([NH:23][C@@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=2)=[C:11]([F:31])[CH:12]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cnccc1-c1ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
(S)-methyl-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinate (50.0 mg, 0.112 mmol) was taken in a mixture of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL). To the solution was added lithium hydroxide (8.05 mg, 0.336 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and the pH adjusted to 4 using 1.5N aqueous HCl. The crude product from the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford (S)-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinic acid (30 mg, 0.060 mmol, 53% yield) as an off-white solid. LC/MS (ESI) m/e 433.2 [(M+H)+, calcd for C23H30FN2O5 433.2]; LC/MS retention time (method C): tR=1.74 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17](OS(C2C(C)=CC=CC=2)(=O)=O)=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH3:56][O:57][C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[C:59]=1B(O)O>O1CCOCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:15]=[CH:16][C:17]([C:59]2[C:58]([O:57][CH3:56])=[CH:63][CH:62]=[CH:61][C:60]=2[O:64][CH3:65])=[CH:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OS(=O)(=O)c2ccccc2C)cc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cccc2OC)cc1
Temperature: 70 °C
Reaction time: 9 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, methyl N-(t-butyloxycarbonyl)-2-amino-2-(4-toluenesulfonyloxyphenyl)acetate (0.44 g, 1.0 mmol), cesium carbonate (0.65 g, 2.0 mmol), tricyclohexylphosphine (0.059 g, 0.2 mmol), bis(1,5-cyclooctadiene)nickel (0.028 g, 0.1 mmol) and 2,6-dimethoxyphenylboronic acid (0.36 g, 2.0 mmol) were mixed in dioxane (1 ml). The reaction mixture was heated to 70° C. and then stirred at the same temperature for 9 hrs. After the reaction was completed, the mixture was left to cool to room temperature and insoluble substances were filtered off. The filtrate was subjected to column chromatography purification to obtain methyl N-(t-butyloxycarbonyl)-2-amino-2-[4-(2,6-dimethoxyphenyl)phenyl]acetate (0.29 g, yield 72%) as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[N:33]1([C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.[Cl-].[Na+].O>[N:33]1([C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[NH:41][C:8]([C:6]2[NH:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: N#Cc1ccc(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccccc2N2CCCCC2)[nH]1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 45.3 %

Procedure:
To 24.5 mg (0.180 mmol) 5-cyano-1H-pyrrole-2-carboxylic acid (as prepared in the previous step) in dichloromethane (10 mL) was added 53 mg (0.28 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), hydroxybenzotriazole (HOBt, 30 mg, 0.22 mmol), and 2-piperidinoaniline (38 mg, 0.22 mmol) and the mixture stirred for 6.5 h at RT. The mixture was poured into brine (50 mL) and extracted with dichloromethane (3×20 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4 and the solvent was removed in vacuo. Purification of the resulting residue by silica gel preparative TLC eluting with 30% ethyl acetate in hexane yielded 24 mg (42%) of the title compound as a brown solid. 1H-NMR (400 MHz, CDCl3): δ 11.90 and 10.45 (br s, 1H, rotomers), 9.60 and 9.38 (s, 1H, rotomers), 8.60 and 8.47 (d, 1H, J=7.9 Hz, rotomers), 7.29-6.74 (m, 5H), 2.85 (m, 4H), 1.78-1.68 (m, 6H). LC-MS (ESI, m/z): Calcd. for C17H19N4O, 295.2 (M+H); found: 295.2.