Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:26]([CH2:40][O:41]C(=O)C)=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[CH2:40][OH:41]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(=O)OCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(CO)c(Cl)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 169.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and acetic acid 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (Stage 238.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.27 min (Method A); M+H=435 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.65-8.62 (m, 1H), 8.18-8.11 (m, 2H), 8.05-8.00 (m, 1H), 7.97-7.94 (m, 1H), 7.58-7.55 (m, 1H), 5.30 (t, 1H), 4.67 (d, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reaction time: 6 h
Yield: 56.8 %

Procedure:
To 30 ml of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml of ethylacetate, which was washed with water (40 ml×2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57%).
Reaction SMILES: [N+]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.[H][H]>[Pd].CO>[C:9]1([CH:4]([CH2:5][OH:6])[CH2:7][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])C(CO)(CO)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCC(CO)c1ccccc1

Procedure:
12 g. (0.06 mole) of 2-nitro-2-phenyl-1,3-propanediol, 400 mg. of 5% palladium on calcium carbonate and 150 ml. of methanol are placed in a Parr hydrogenator bottle and reduced with hydrogen overnight. The mixture is filtered through Celite, concentrated to an oil and recrystallized from 30 ml. of toluene. The yield is 7.4 g. (80%) of product, M.P. 52°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].I[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH2:26])[N:19]([CH:27]([CH3:29])[CH3:28])[N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:27]([N:19]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:26])=[C:25]2[C:17]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[N:18]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cc(B(O)O)cc(OC)c1OC
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: COCCOC
Solvent: CCO
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)cc(OC)c1OC
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of 3,4,5-trimethoxyphenylboronic acid (123 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA64 (70 mg, 89% yield). ESI-MS (M+H)+ m/z calcd 344.1, found 344.0.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[OH-].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 30 g of 2-(4-chlorophenoxymethyl)-2-tert.-butyloxirane, 9.8 g of 1,2,4-triazole and 1.2 g of solid potassium hydroxide in 70 ml of toluene and 7.5 ml of dimethyl sulphoxide was heated under reflux for 6 hours. After cooling to room temperature, 2 g of silica gel were added to the reaction mixture and it was then filtered. 75 ml of semi-concentrated hydrochloric acid were added to the filtrate, and the crystals which separated out thereby were filtered off with suction. Then 80 ml of water and aqueous sodium hydroxide solution were added to the crystalline solid so that the pH of the mixture was 13. It was stirred a further 2 hours at room temperature, then filtered off with suction and washed with water to neutrality. In this manner, 20 g (52% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 84°-87° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:9]1([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:15]#[N:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
To a cold (0° C.) solution of 2-chloropyridine (4.8 mL, 50 mmol) and benzyl cyanide (5.8 ml, 50 mmol) in 120 ml of DMF, was added with potassium t-butoxide (11.2 g, 100 mmol), under N2. The reaction mixture was reacted for 3 hours and then partitioned between EtOAc and H2O. The resulting layers were separated and the EtOAc layer was washed sequentially with NaHCO3 and brine, dried over Na3SO4, filtered and concentrated in vacuo. The crude material was purified by recrystallization (hexanes/EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]C)=[O:21]>C(#N)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH2:19][C:20]([OH:22])=[O:21])=[C:4]([F:11])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1OCC(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (4.57 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (12.66 mmol). The reaction mixture was stirred for 30 min and was then treated with methyl bromoacetate (5.48 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring for 2 h. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude title product. The beige solid was used without further purification (1.05 g, 83% yield). MS(ES)+ m/e 276.9, 278.9 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])=[CH:5][CH:4]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 75.0 g (431 mmol) of 4-(trifluoromethyl)benzaldehyde in 750 ml of diethyl ether was slowly added dropwise to 517 ml (517 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at RT under argon. After heating under reflux for 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 9/1) to result in 87.0 g (100% of theory) of the title compound.
Reaction SMILES: C([O-])(=O)C.[CH2:5]([P+:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].O.O.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].C(O)(=O)C(O)=O>CO>[C:28]([O-:33])(=[O:32])[C:29]([O-:31])=[O:30].[CH2:5]([P+:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6].[CH2:5]([P+:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6]
Reactant: O=C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: O=C([O-])C(=O)[O-]

Procedure:
To a 2 gallon bottle was charged 1000 g (1.707 mol) of a 70% methanol solution of ethyltriphenylphosphonium acetate.acetic acid complex followed by the addition of 204.4 g (1.622 mol) oxalic acid dihydrate. The mixture was mixed until all of the oxalic acid had dissolved and then about 31.5 g of methanol was added to give a resultant solution of about 50 wt. % ethyltriphenylphosphonium oxalate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reaction time: 1.5 h

Procedure:
4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:17][C:18]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:24]4[CH2:23][CH2:22][CH:21]([CH2:20][C:19]5[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:18]=5[F:17])[CH2:26][CH2:25]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(F)c(CC2CCNCC2)c1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Product: COc1ccc(F)c(CC2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 4-(2-fluoro-5-methoxybenzyl)piperidine were reacted as described in in example 9 to give the product (31%, mp: 89°-91° C.). Calc'd for C25H29F2NO2 : C, 72.61%; H, 7.07%; N, 3.39%. Found: C, 72.66%; H, 7.07%; N, 3.30%.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.273 mmol), 4-methoxyphenylsulphonyl chloride (57 mg, 0.273 mmol), and diisoproylethylamine (0.0476 mL, 0.273 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred under Argon for 16 hours at ambient temperature. A catalytic quantity of 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately two hours. After cooling, the reaction was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with aqueous potassium carbonate (5% w/v), aqueous hydrochloric acid (1N) and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 NM) eluting with 95:5 methylene chloride:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was purified again on a preparative TLC plate (20×20 cm, 500 μM) eluting with 95:5 methylene chloride:ethyl acetate. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo to provide tert-butyl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 70%) as a foam. H1-NMR (chloroform-D3): 0.95 (m, 6H), 1.38 (s, 9H), 1.64 (m, 4H), 3.01 (m, 5H), 3.83 (m, 2H), 3.93 (s, 3H), 4.20 (m, 1H), 4.61 (m, 1H), 7.03 (d, 2H), 7.29 (m, 5H), 7.80 (d, 2H). MS(ESI): 559(M+Na).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1cc(Cl)ccc1B(O)O
Product: COc1cc(Cl)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 32 was prepared under similar conditions as described in the preparation of Example 30 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-chloro-2-methoxyphenyl)boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:15][CH:13]1[CH3:14]>C(O)(C)C>[OH:15][CH:13]([CH3:14])[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CC1CO1
Solvent: CC(C)O
Product: CC(O)CN1C(C)(C)CC(O)CC1(C)C
Temperature: 160 °C

Procedure:
A mixture of 3.14 parts of 2,2,6,6-tetramethylpiperidin-4-ol, 10 parts of propylene oxide and 10 parts of isopropanol was charged to an autoclave. A pressure of 100 atmospheres of nitrogen was applied and the mixture heated at 160°C for 6 hours. The isopropanol solvent and unreacted propylene oxide were removed by distillation under reduced pressure. Crystallisation of the residue from cyclohexane gave 3.0 parts of 1[2-hydroxypropyl]-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 97°-8°C and on further purification of 107°-8°C and the following elemental analysis by weight:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (14 mg, 14%), MS (ISP) m/z=415.4 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 1-hydroxy-cyclopropane-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:22]I.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:22])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 20.0 9 (0.07 mol) of N-[2-(3,4-dimethoxyphenyl)ethyl]trifluoroacetamide to a suspension of 3.17 g (0.08 mol) of 60% sodium hydride in 50 mL of dry tetrahydrofuran. Stir this suspension for 30 minutes at room temperature. After 30 minutes, add 6.72 mL (0.11 mol) of methyl iodide and stir at room temperature for one h. After one h, filter reaction mixture and make basic (pH=14) with 4N sodium hydroxide. Wash this mixture with 2×100 mL of water. Extract the combined aqueous washes with 2×100 mL of methylene chloride. Wash the combined organic extracts with 6N hydrochloric acid, then with 100 mL of water. Dry the organic layer over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and methanamine hydrochloride (13.2 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 23.8 mg (30%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.20 (d, J=4.5 Hz, 1H), 7.92 (dd, J=9.0, 2.1 Hz, 1H), 7.65 (s, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.77-3.94 (m, 1H), 3.56 (d, J=2.3 Hz, 4H), 3.34 (s, 2H), 2.74 (d, J=4.5 Hz, 3H), 2.53-2.69 (m, 1H), 2.41 (br. s., 4H), 1.99-2.08 (m, 1H), 1.84 (br. s., 1H), 1.59-1.69 (m, 1H), 1.31-1.57 (m, 3H). [M+H] calc'd for C25H33N7O2, 436. found, 436.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:19])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (140 mg, 0.58 mmol) in DCM (5.8 mL) was added acetic anhydride (82 μL, 0.87 mmol) and triethylamine (244 μL, 1.75 mmol) and the reaction mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (6 mL), washed with water (3×4 mL) and brine (1×4 mL). The organic layer was dried, filtered and concentrated in vacuo to provide 7-acetyl-2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester as a brown oil (164 mg, 100%). This intermediate was dissolved in DCM (0.75 mL), treated with HCl (4M in dioxane, 0.75 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to yield then desired product (128 mg, 100%). MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OC/C=C/c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(/C=C/CCl)cc1
Reaction time: 0.5 h

Procedure:
(2E)-3-(4-Fluorophenyl)prop-2-en-1-ol (1.36 g) synthesized in Reference Example 24 was dissolved in dichloromethane (45 mL), pyridine (0.78 g) and thionyl chloride (0.72 mL) were added under ice-cooling, and the mixture was stirred for 30 min. The mixture was diluted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane) to give the title compound (1.1 g) as a colorless oil.