Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)(=[O:21])[CH3:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[C:19](=[O:21])[CH3:20])[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: CC(=O)c1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-acetylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 348.0 (M+H)+, retention time 1.26 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24]#[CH:25])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([C:16]1[CH:25]=[C:24]([CH:23]([O:26][CH2:27][CH3:28])[O:22][CH2:20][CH3:21])[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(OCC)OCC
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(OCC)c1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 52.4 %

Procedure:
A mixture of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (1.2 g, 4.5 mmol), 3,3-diethoxy-propyne (1.5 g, 11.4 mmol), CH2Cl2 (40 ml) and TEA (6 drops) was stirred until homogeneous, then Clorox bleach (20 ml) was added. After stirring vigorously for 12 h the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4; filtered; and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40(small) chromatography eluting with 10% EtOAc in hexanes gave 920 mg of the title compound as a colorless oil. MS [M+1]+ 391.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:44][CH3:45])[C:3]([O:5][CH:6]1[CH:15]2[C:10]([CH:11]=[CH:12][CH:13]([CH3:42])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([O:24][C:25](=[O:40])[CH2:26][CH2:27][C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=O)[NH2:38])=[CH:33][CH:32]=3)=[O:29])[CH2:21][C:20](=[O:41])[O:19]2)=[CH:9][CH:8]([CH3:43])[CH2:7]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:56])=CC=1>C1C=CC=CC=1>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH:22]2[CH2:21][C:20](=[O:41])[O:19][CH:18]([CH2:17][CH2:16][CH:14]3[CH:15]4[C:10](=[CH:9][CH:8]([CH3:43])[CH2:7][CH:6]4[O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:44][CH3:45])[CH:11]=[CH:12][CH:13]3[CH3:42])[CH2:23]2)=[O:40])=[CH:32][CH:33]=1)(=[S:56])[NH2:38]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(OC(=O)CCC(=O)Oc4ccc(C(N)=O)cc4)CC(=O)O3)C21
Solvent: c1ccccc1
Product: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(OC(=O)CCC(=O)Oc4ccc(C(N)=S)cc4)CC(=O)O3)C21
Temperature: 50 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
Succinic acid 4-carbamoyl-phenyl ester 2-{2-[8-(2,2-dimethyl-butyryloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl]-ethyl}-6-oxo-tetrahydro-pyran-4-yl ester (2) (0.35 g, 0.000548 mol) and Lawesson reagent (0.221 g, 0.000548 mol) were dissolved in 30 ml of anhydrous benzene. The reaction was warmed to 50° C. and stirred for 6 h. The solvent was removed under reduced pressure; the crude residue was purificated by silica gel column (dichloromethane/methyl alcohol 9.5:0.5) to furnish 35 mg of the pure compound 3 (10% yield).
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][C@@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13]O)([CH3:4])[CH3:3].S(Cl)(C)(=O)=O.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:3][C:2]([Si:5]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][C@@H:8]1[CH2:9][C@H:10]2[C@H:11]([CH2:12]2)[CH2:13][N:15]1[C:16]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25])([CH3:4])[CH3:1]
Reactant: CC(C)(C)[Si](OC[C@H](CC1CC1CO)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice cooled solution of phenylmethyl ((1S)-2-{[(1,1 dimethylethyl)(diphenyl)silyl]oxy}-1-{[2-(hydroxymethyl)cyclopropyl]methyl}ethyl)carbamate single diastereoisomer 1 D7 (1.18 g) in DCM (35 ml) and TEA (0.953 ml, 6.84 mmol) was added mesyl chloride (0.355 ml, 4.56 mmol) and the resulting mixture was stirred for 3 hours. After this time the solvent was removed under reduced pressure and the white solid obtained was dissolved in DMF (47 ml), the solution was cooled to 0° C. and NaH (0.730 g, 18.25 mmol, 8 eq) was added and ice bath was removed. After stirring overnight more NaH (0.365 g, 9.12 mmol, 4 eq) was added to the ice cooled mixture and stirred at room temperature for 3 hours. UPLC showed starting material and desired product in 1:1 ratio, so NaH (0.180 g, 4.5 mmol, 1.97 eq) was added at room temperature and stirred for 2.5 hours. A saturated solution of NH4Cl (300 ml) was added and extracted with EtOAc (3×50 mls), the organic phase was separated, dried (Na2SO4), filtered and evaporated to give a yellow oil which was purified via Biotage SP4 (silica gel, SNAP 100 g column; eluted with a gradient of Cy/EtOAc from 1/0 to 9/1). Collected fractions gave the title compound D8 (0.930 g) as a colourless oil. MS: (ES/+) m/z: 500 (M+1). C31H37NO3Si requires 499. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.76-7.31 (m, 15 H), 5.16-4.84 (m, 2 H), 4.37 (br.s, 1 H), 3.83-3.68 (m, 1 H), 3.68-3.52 (m, 2 H), 2.37-2.22 (m, 2 H), 1.39-1.18 (m, 1 H), 1.13-1.01 (m, 1 H), 0.95 (s, 9 H), 0.92-0.83 (m, 1 H), 0.79-0.70 (m, 1 H), 0.33-0.04 (m, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>[Pd].C(O)C.CO>[CH2:36]([O:35][CH2:34][C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:37]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Yield: 87.7 %

Procedure:
A mixture of tert-butyl 4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate (15 g, 29.7 mmol) and 10% palladium on carbon (4.5 g, wetted with ethanol) in 1:1 ethanol/methanol (400 mL) was hydrogenated using a Parr apparatus at 28 psi (1.9×105 Pa) for 16 hours. The mixture was filtered through CELITE filter agent, which was subsequently washed with methanol. The filtrate was concentrated under reduced pressure to afforded 10.8 g of tert-butyl 4-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate as a green-yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]), and 0.483 g (3.52 mmol) 4-ethoxyaniline is heated for 30 min at 90° C. The cooled reaction mixture is distributed with thorough stirring between a dichloromethane/methanol mixture (18:1) and saturated aqueous sodium carbonate solution. The organic phase washed with water and brine is dried over anhydrous sodium sulfate and evaporated under vacuum. Title compound is obtained after recrystallization of the residue from acetate/methanol and acetonitrile; m.p. 223-224° C.; ESI-MS: (M+H)+=357.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][CH:13]([F:16])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCC(F)F
Product: O=C(O)c1cnc(OCC(F)F)c(Cl)c1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (4.12 g, a white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]\OCC)[C:5]([F:13])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:29][C:28]1[C:23]2[N:24]([C:8]([C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:9][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ncccc1Cl
Reactant: CCO/C=C\c1nc(Cl)ncc1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cnc(Cl)nc1-c1cnc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
25.2 g of the compound [67-1] was dissolved in a mixed solvent of 320 mL of 1,4-dioxane and 32 mL of water. Then, 22.2 g of N-bromosuccinic acid imide was added under an ice-cold condition, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 16.0 g of 2-amino-3-chloropyridine was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The obtained organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, hexane was added, and the mixture was stirred for 30 minutes. The solid was taken by filtration, and dried under reduced pressure to obtain 20.0 g of 8-chloro-3-(2-chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine [67-2] (hereinafter, referred to as the compound [67-2]) as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn:19]>O.[OH-].[Na+]>[Zn:19].[C:1]1([S:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O-:18])=[O:17])[CH2:14][CH2:15]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: O=C([O-])C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
12.12 g (0.045M) of N-benzenesulfonylpiperidine-4-carboxylic acid were dissolved in 250 ml of water with the addition of 22.5 ml of 4N NaOH at 50° C. Thereafter, 2.94 g (0.045M) of ZnSO4.7H2O, dissolved in 100 ml of water, was slowly added at 50° C. After the mixture had been stirred for 3 1/2 hours at 50° C., the resulting pH was 7.3. The mixture was then stirred at room temperature, and the product was filtered off under suction, washed and dried. 15.8 g of a product which contained 1.05 moles of Zn per mole of starting acid resulted.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](Cl)=[O:13]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:19])[C:3]=2[CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Product: COc1ccc2c(c1)C(=O)c1ccccc1C2=O
Yield: 79.8 %

Procedure:
The method was similar to that in Example 1, using 10.8 g (0.1 mols) of anisole and 20.2 g (0.1 mols) of phthalic acid dichloride. The product was 19.0 g (60% yield) of 2-methoxy-9,10-anthraquinone (13), m.p. 195°-197° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)[CH2:44][C:40]1[NH:39][CH:43]=[CH:42][N:41]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The compound (20.4 mg) obtained in Example 35-5 was dissolved in anhydrous methanol (2.0 ml) and added with sodium cyanoborohydride (9.50 mg), acetic acid (2.0 ml), and 2-imidazole carboxaldehyde (9.60 mg), followed by stirring at room temperature under a nitrogen atmosphere for 6.5 hours and a half. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (4.50 mg) of the subject compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCCNCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl bromoacetate (1.64 mL, 11.1 mmol) was added into a mixture of 4-{[(2-methoxyethyl)amino]methyl}benzonitrile (958 mg, 5.04 mmol) and K2CO3 (3.06 g, 22.2 mmol) in ACN (20 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, and then washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil. LC/MS (Method B): 305.1 (M+H)+. HPLC (Method A) Rt 3.09 min (Purity: 91.1%).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (350 mg, 1.38 mmol) and 1-bromooctadecane (1.15 g, 3.45 mmol), alcohol 46 was obtained as a colorless oil (395 mg, 56% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24](Br)CC>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:24][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(Br)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccccc21
Yield: 80.6 %

Procedure:
A solution of dry acetone (100 mL) containing N-(tertbutoxycarbonyl)-2-aminophenol (0.722 g, 3.69 mmol), potassium carbonate (10.2 g, 73.8 mmol) and 1,2-dibromobutane (2.54 mL, 29.6 mmol) was refluxed for 18 h. The reaction was monitored by TLC (petrol/ether 8/2). After cooling, the mixture was filtered through celite. After concentration and hydrolysis, the aqueous layer was extracted with EtOAc (3×40 mL), dried over MgSO4 and the solvent was removed under reduce pressure. The crude product was purified by flash chromatography on silica gel (petrol/EtOAc 95/5) to yield the title compound as a white solid (0.70 g, 82%). m.p=78-79° C.; Rf=0.44 (petrol/ether 8/2); LCMS m/z 236 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 1.59 (9H, s); 3.87 (4H, m); 4.26 (4H, m); 6.86-7.02 (4H, m); 13C NMR (75 MHz, CDCl3): δ 27.4 (3C); 41.1; 64.6 (2C); 80.6 (2C); 116.0; 119.2; 122.6; 123.4; 125.2; 144.9; 151.6. IR (film): 2975; 1696; 1494; 1143 cm−1.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[O:40]1[CH2:41][CH2:42][CH:37]([NH:36][C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38][CH2:39]1
Reactant: NC1CCOCC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)NC1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 4-aminotetrahydropyran hydrochloride (Combi-Blocks and Cat. No. AM-1014). LCMS (M+H)+: m/z=557.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25]([CH:30]=O)=[N:26][CH:27]=[CH:28][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:30][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-[(3-methyl-pyridin-2-ylmethyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester, 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.84-1.88 (m, 4H), 2.09 (s, 6H), 2.50-2.66 (m, 3H), 3.81 (s, 4H), 4.14-4.17 (m, 2H), 7.05-7.09 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.34 (d, 2H, J=3.0 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 249 as a white solid. 1H NMR (CDCl3) δ 1.56-1.70 (m, 2H), 1.75 (s, 1H), 1.90 (d, 2H, J=12.0 Hz), 2.10 (s, 6H), 2.31-2.51 (m, 2H), 2.55-2.58 (m, 1H), 3.12 (d, 2H, J=12.0 Hz), 3.84 (s, 4H), 7.05-7.09 (m, 2H), 7.35 (d, J=7.5 Hz), 8.34 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.42, 28.86, 47.07, 55.13, 58.17, 122.64, 133.81, 138.29, 146.21, 157.93. ES-MS m/z 311 (M+H). Anal. Calcd. for C19H26N4.0.3H2O: C, 72.25; H, 8.49; N, 17.74. Found: C, 72.11; H, 8.41; N, 17.58.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1C=Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 43 h
Yield: 90.5 %

Procedure:
To a solution of (2R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-2H-chromene (120 mg, 0.361 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.361 g, 1.084 mmol) and the reaction mixture stirred at room temperature for 43 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 5% ammonia saturated methanol solution in dichloromethane gave 100 mg (90%) of {[(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (2 mL), a solution of hydrogen chloride (1.0 M in diethyl ether, 0.326 mL, 0.326 mmol) was added followed hexane (7 mL). The resulting white precipitate was filtered to afford 100 mg (80%) of {[(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl}amine hydrochloride as an off-white solid.