Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)CC2C=CC(OC)=CC=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:33][CH2:34]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CCO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(CCO)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg, 0.046 mmol) was taken up in DCE (0.5 mL) and anisole (10.06 μl, 0.092 mmol) was added, followed by TFA (0.142 mL, 1.842 mmol). The reaction was heated at 50° C. for 2 h. The solvent was removed in vacuo and the material dissolved in 2N NH3 in MeOH. The solution was stirred for 10 min to cleave the ester, and the solvent was removed in vacuo. The material purified by preparative HPLC. 2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.7 mg) was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[N:13]=2)=[CH:8][C:7]=1[Cl:26])(=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C.O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:14]1[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[C:7]([Cl:26])[CH:8]=2)[N:16]([CH3:17])[N:15]=1
Reactant: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
5-(4-acetoxymethyl-3-chlorophenyl)-3(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (11.1 g) is dissolved in a mixed solvent of ethanol (50 ml) and water (20 ml), added with sodium hydroxide (2.3 g) and heated under reflux for 1 hour with stirring. After cooling to room temperature, the reaction mixture is added with ethyl acetate and washed with water. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude solid. The crude solid is washed with mixed solvent of hexane-ethanol to give 6.7 g of desired compound (melting point: 111°-113° C.).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(/C=C/C(=O)O)c1
Yield: 28.6 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.7 g of ethyl (E)-3-{3-[2-((2RS,5SR)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}cinnamate in solution in 60 cm3 of methanol and 0.4 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment, 1 g of (E)-3-{3-[2-((2RS,5SR)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}cinnamic-acid is obtained [proton NMR (250 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, preponderant rotamer description, general description valid for the other products of the series: 1.5 (bs, 9H, (CH3)3 ; 1.9 and 2.2 (2m, 4H, H in position 3 and 4 on pyrrolidine); 3.2 and 3.9 (ABX, 2H, CH2N); 4.35 (dd, 1H, H in position 2 on pyrrolidine); 5.20 (dd, 1H, H in position 5 on pyrrolidine); 6.30 (dd, 1H, NH); 6.4 (bd, 1H, J=15, CH= trans); 7.1 to 7.7 (m, 10H, aromatic and CH= trans); (s, 1H, NH). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 3075, 3030, 3700 to 2250 with a maximum at 2475, 2980, 2935, 2875, 1735, 1705, 1695, 1640, 1610, 1590, 1560, 1495, 1450, 1430, 1395, 1370, 1315, 1250, 1225, 1155, 985, 910, 890, 860, 840, 790, 760, 705, 685].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH:25]12[N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:21])([F:23])[F:22])[N:17]=[CH:18][C:13]=34)[CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A suspension of 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.59 g, 1.4 mmol) in tetrahydrofuran (40 mL) and ethyl acetate (10 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (100 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen-filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a white solid (0.51 g, 89%). MS (ES+): 405.0 (M+H)+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1ccc(Br)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
4-Bromophenylhydrazine hydrochloride (15 g), ethyl pyruvate (11 ml) and acetic acid (1 ml) were dissolved in ethanol and heated to reflux for 2 hours, then cooled to room temperature, resulting in precipitation of a yellow solid, which was filtered off and dried in vacuo to give the ethyl pyruvate 4-bromophenylhydrazone (16.3 g, 71%), mp 153-154°; NMR δ (CD3SOCD3) 1.23 (t, 3H), 2.03 (s, 3H), 4.18 (q, 2H), 7.19 (d, 2H), 7.40 (d, 2H), 9.88 (brs, 1H); M/z (−) 285 (M+), 283, 171, 169, 113.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Tertiary butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (48 g, 163.6 mmol) was dissolved in dimethylformamide (500 mL) and sodium azide (19.15 g, 295 mmol) was added thereto, followed by stirring at 120° C. for 6 hours. After the reaction was completed, the reactants were cooled to room temperature, extracted with ethyl acetate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the title compound (35 g, 89%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[CH:17]=[CH2:18]>>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8]1
Reactant: C=CC(=O)OCCCC
Reactant: C1=Cc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOC(=O)CCC1=CCc2ccccc21
Reaction time: 1 h

Procedure:
To a mixture of 4-5 g. of solid potassium t-butoxide in 464 g. (4.0 mole) of indene heated to 120° is added dropwise over 11/2 hours 256 g. (2.0 mole) of n-butyl acrylate at 100°-120°. After 1 hour longer at 120°-150°, the mixture is cooled, treated with 25 ml. acetic acid and filtered. Distillation affords 256 g. (57%) of product collected at 143°-160° (2 mm. torr.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([OH:21])([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:6]([CH3:24])[CH:5]=1.I[CH3:26]>O1CCOCC1>[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([O:21][CH3:26])([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:6]([CH3:24])[CH:5]=1
Reactant: CI
Reactant: Cc1cc(Cl)ccc1OCC(O)(Cn1cncn1)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(COc1ccc(Cl)cc1C)(Cn1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.3 %

Procedure:
27 g (0.9 mol) of 80% strength sodium hydride were introduced in portions into a solution of 290 g (0.86 mol) of 2-(4-chloro-2-methyl-phenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol in 1,600 ml of absolute dioxane at room temperature. The mixture was subsequently stirred at room temperature for 4 hours, and 141.9 g (1 mol) of iodomethane were then added dropwise. The reaction mixture was stirred at 40° C. for 12 hours and another 10 g (0.33 mol) of 80% strength sodium hydride were then added in portions. After the mixture had been stirred at room temperature for three hours, 57 g (0.4 mol) of iodomethane were added and the reaction mixture was subsequently stirred at room temperature for 72 hours. The suspension was filtered, the filtrate was concentrated, the oily residue was taken up in methylene chloride and the methylene chloride mixture was washed twice with water, dried over sodium sulphate and concentrated. 1,5-Naphthalenedisulphonic acid was added to the residue, in acetone, the salt which precipitated was filtered off with suction, washed with acetone and suspended in methylene chloride, and saturated sodium bicarbonate solution was added. The organic phase was separated off, washed and concentrated. 155 g (54% of theory) of 2-(4-chloro-2-methyl-phenoxymethyl)-3,3-dimethyl-2-methoxy- 1-(1,2,4-triazol-1-yl)butane were obtained as a light yellow oil of refractive index nD20 =1.5390.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:18]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=O)[CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1.O>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:18]([CH2:21][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][CH3:20])[CH3:17])=[CH:13][CH:14]=1
Reactant: CCN(C(=O)C1CCNCC1)C(C)Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1

Procedure:
A solution of lithium aluminum hydride (30 mmole) in tetrahydrofuran (120 ml) was heated under reflux. A solution of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylcarbonyl)amine (7.8 grams, 25.6 mmole) in tetrahydrofuran (40 ml) was added dropwise. After 30 minutes excess water was added at 22° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine, which was isolated as the hydrochloride salt from acetonitrile (7.0 grams, 75%), m.p. 144-146° C., M+H 405.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.CCN(C(C)C)C(C)C.CC(=O)OCC.CCCCCCC>CCO.CC(=O)OCC>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:19]2[N:20]=[CH:21][C:16]([Br:15])=[CH:17][N:18]=2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(Br)cn2)C1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of (R)-3-amino-1-N-Boc-piperidine (920 mg) in dry EtOH (20 mL) were added successively 5-bromo-2-chloropyrimidine (957 mg), DIEA (0.86 mL). The reaction mixture was stirred at reflux for 16 hours under nitrogen. After cooling to RT, the reaction mixture was diluted with EA, washed with sat. NaHCO3, 1N NaOH. The organic extract was dried (MgSO4), filtered and concentrated to yield a crude brown-orange oil. FC (EA/n-heptane: 2/8) gave 787 mg (48%) of the title compound as a light brown solid.
Reaction SMILES: C1(C)C=CC=CC=1.[Na].[CH3:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-])=[O:17]>CO>[CH3:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: CC(C)CCCCCC(=O)[O-]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)CCCCCCO
Yield: 105.9 %

Procedure:
In a similar reaction as in 1 above, 100 ml toluene, sodium (39.5 g, 1.72 mole), 7-methyl-octanoate (52 g, 0.29 mole), and 260 ml anhydrous methanol reacted to yield 7-methyl-1-octanol (44.3 g, yield rate 85%); 7-methyl-1-octanol (44.3 g, 0.31 mole) reacted with chloro-chromic pyridine (100 g, 0.465 mole) to yield 7-methyl-octanaldehyde (31 g, yield rate 70%); and finally, 7-methyl-octanaldehyde (20 g, 0.14 mole), malonic acid (15 g, 0.14 mole), and 15 ml pyridine were added together and refluxed with heating for 3 hours. After cooling down 15 ml 30% sulfuric acid was added and the reaction mixture was stirred for 3 hours under ice bath and then extracted by diethyl ether. Diethyl ether was removed by evaporation and product was subject to vacuum fractional distillation and 122° C./1.5 mmHg fraction was collected as 9-methyl-2-decenoic acid (16 g, yield rate 80%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18]C)[C:6]1=[O:7])[CH2:2][CH2:3]C.Br[CH2:21][CH2:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][P:24](=[O:28])([O:29][CH2:30][CH3:31])[O:25][CH2:26][CH3:27])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:7])[CH2:2][CH3:3]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Product: CCCn1c(=O)c2c(ncn2CCCP(=O)(OCC)OCC)n(CCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 3-bromopropanephosphonate analogously to Example 9.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:7]([NH2:10])=[N:8][CH:9]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21]Cl>CN(C)C=O>[Br:3][C:4]1[N:5]=[C:6]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:7]([N:10]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:8][CH:9]=1
Reactant: Nc1ncc(Br)nc1OCC1CCC1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCCC2)c(OCC2CCC2)n1
Reaction time: 16 h
Yield: 59.6 %

Procedure:
Sodium hydride (0.98 g, 25.6 mmol) was added in portions to a solution of 5-bromo-3-cyclobutylmethoxy-pyrazin-2-ylamine (3.1 g, 12.2 mmol) in N,N-dimethylformamide (60 mL) under nitrogen at room temperature. After 20 minutes 1-bromo-4-chlorobutane (1.5 mL, 13.4 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was poured onto ice and the whole was extracted with ethyl acetate (50 mL) and washed with water (30 mL×2), the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (30% ethyl acetate/heptane) to afford 5-bromo-3-cyclobutylmethoxy-2-pyrrolidin-1-yl-pyrazine as a yellow solid 2.27 g (60% yield). LC@215 nm; Rt 2.72: 100%, m/z (ES+): 313 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:5][CH2:4]1.I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:5][CH2:4]1)([CH3:26])[CH3:25]
Reactant: COc1ccccc1-c1csc(NC2CCC(CN)CC2)n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1csc(NC2CCC(CNC(C)C)CC2)n1
Temperature: 50 °C
Yield: 53 %

Procedure:
The reaction mixture of N-[4-(aminomethyl)cyclohexyl]-4-(2-methoxyphenyl)-1,3-thiazol-2-amine (1 equivalent), 2-iodopropane (1 equivalent), and potassium carbonate (2 equivalents) in DMF was heated at about 50° C. overnight. Water was then added to the reaction mixture and extracted with diethyl ether (3 times). Evaporation of the combined organic phase afforded a yellow oil which was purified by preparative TLC plates. The desired product was obtained as a yellow oil in 53% yield: ESIMS m/e=360 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[N:22][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:16])=[N:20][CH:19]=1
Reactant: CNCCNc1ncc(Br)cn1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N(C)CCNc2ncc(Br)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4carboxylic acid (78 mg, 0.33 mmol) and N-(5-bromo-pyrimidin-2-yl)-N′-methyl-ethane-1,2-diamine, D11 (76 mg, 0.33 mmol), according to the procedure described for Example 1, as a solid (105 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][C:8](=[CH2:11])[CH2:7][CH2:6]1)=[O:4].[OH:33]O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH2:11][OH:33])[CH2:7][CH2:6]1)=[O:4]
Reactant: OO
Reactant: C=C1CCC(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(CO)CC1
Temperature: -25 °C
Reaction time: 8 h

Procedure:
The compound of step 1 of example 56 (500 mg, 1.14 mmol) was dissolved in THF (5 ml) and cooled to −25° C. Borane-tetrahydrofuran complex (2.29 ml of a 1 M solution in THF, 2.29 mmol) was added and the mixture was kept overnight at 0° C. Hydrogen peroxide (2.5 ml, 30% in water) and sodium hydroxide (2.5 ml, 20% in water) were added sequentially and stirring was continued at room temperature. The mixture was partitioned between water and EA, the aqueous phase extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[C:4](=[O:9])[N:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g), 7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N,O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70° C. for 1 hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-185° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (br s, 1H), 8.11 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.02-6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(C)C=CC=CC=1>C(OCC)C>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:17]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 5.60 g (0.03 mole) of the known compound 4-amino 2,6-di-t-butylphenol in 100 ml of diethyl ether was added dropwise over a period of twenty minutes to a solution of 4.44 g (0.03 mole) of phthalic anhydride in 200 ml of a 1:2 mixture of diethyl ether:toluene. The reaction mixture was stirred at room temperature for about sixteen hours. The resulting precipitate was collected, rinsed with a mixture of diethyl ether and hexane, and dried to give 6.8 g of a white solid. This material was recrystallized from a mixture of ethyl acetate and hexane to give 5.9 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl)carbamoyl]benzoic acid, m.p. 191°-192° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4, %N, 3 8; Found: %C, 71.8; %H, 7.3; %N, 3.7.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1
Reactant: COCCc1ccc(OCC2CO2)cc1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: COCCc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 10.4 g of 1-[p-(2-methoxyethyl)-phenoxy]-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(p-(2-methoxyethyl)-phenoxy)-2-hydroxypropyl]4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 113°-115° C.