Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C@@H:7]([NH:11][C:12]([O:14]CC1C=CC=CC=1)=O)[CH2:8][O:9][CH3:10].C>CO>[CH3:10][O:9][CH2:8][C@@H:7]1[NH:11][C:12](=[O:14])[CH2:4][NH:5][CH2:6]1
Reactant: COC[C@@H](CNCC(=O)OC)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC[C@H]1CNCC(=O)N1
Reaction time: 5 h
Yield: 82.7 %

Procedure:
(R)-(2-Benzyloxycarbonylamino-3-methoxy-propylamino)-acetic acid methyl ester (3.9 g, 12.58 mmol) is dissolved in MeOH (˜200 mL) and warmed in the presence of decolorizing charcoal for 1 h. The mixture is filtered through celite and the clear filtrate is concentrated. The residue is redissolved in MeOH (160 mL) and placed in a Parr bottle. Palladium-on-carbon (10%, 800 mg) is added and the mixture is hydrogenated for 5 h at 45 PSI. An additional portion of Pd-on-C (250 mg) is added and the mixture left is reacted for 16 h at 45 PSI. The mixture is filtered through celite and concentrated to afford 1.5 g (83%) of (R)-6-methoxymethyl-piperazin-2-one as a yellow solid which is used without further purification. 1H NMR (300 MHz, CDCl3) δ1,77 (br s, 1H), 2.70 (dd, J=13.1, 7.2 Hz, 1H), 3.07 (dd, J=13.1, 4.5 Hz, 1H), 3.26 (dd, J=9.1, 7.7 Hz, 1H), 3.33 (s, 3H), 3.37-3.45 (m, 3H), 3.61 (m, 1H), 6.51 (br s, 1H) ppm.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([O:13][C:14](Cl)=[O:15])([CH3:12])[CH3:11]>O>[C:4]1([NH:3][C:14](=[O:15])[O:13][CH:10]([CH3:12])[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)OC(=O)Nc1ccccc1

Procedure:
Six hundred and seventy (670) pounds of 50 percent aqueous sodium hydroxide solution were added to one hundred and fifty (150) gallons of water contained in a reactor kettle equipped with a stirrer, heating, and cooling means. The temperature was maintained below 60° F., and the solution was continuously stirred. Seven hundred and fifteen (715) pounds of aniline were then added; the temperature was lowered to 50° F. and the pH of the solution was adjusted to between 7.0 and 8.0 and maintained thereat while one thousand and fifty (1050) pounds of isopropylchloroformate were added to form isopropyl N-phenylcarbamate. When 99 to 99.5 percent of the aniline had reacted, the reaction mixture was pumped into a wash kettle and heated with stirring to about 185° to 210° F. until about 95 percent of the isopropyl N-phenylcarbamate had melted. The stirring was stopped, and the mixture was allowed to separate into two phases, the lower of which, i.e., the aqueous salt phase, was drained away. An equal volume of hot water (200° F.) was added to the remaining phase comprised primarily of molten isopropyl N-phenylcarbamate, and the mixture was agitated for 20 minutes, and then allowed to separate into two phases. The upper phase comprising washed molten isopropyl N-phenylcarbamate was pumped into a second wash kettle and washed with 200 gallons of dilute hydrochloric acid solution maintained at 185° F. The washing of the mixture in the second wash kettle was continued, until a 25 milliliter sample of the wash kettle showed that a 1/2 inch cube of solid isopropyl N-phenylcarbamate heated and mixed with 25 milliliters of distilled water gave no color or only a slight bluish tinge when 3 drops of a solution containing 5 grams of calcium hypochlorite per 100 milliliters of water were added to the mixture of water and isopropyl N-phenylcarbamate after the mixture was cooled to ambient temperature (65° F.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]#[N:24])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]([Sn](CCCC)(CCCC)CCCC)=[N+:41]=[N-:42]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:25][C:26]2[CH:27]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=2)[C:23]2[N:40]=[N:41][NH:42][N:24]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.61 mmol) in toluene (10 mL), add azidotributyltin (3.22 mmol) and heat to 100° C. After stirring for 12 h, cool the reaction to room temperature and quench with methanol (1 mL). Dilute the reaction mixture with ethyl acetate (100 mL) and wash with aqueous sodium fluoride (50 mL) and brine (50 mL). Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (1-5%) to afford the title compound as a colorless foam. MS (ES+): 597.3 (M−H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[OH-]>N1C=CC=CC=1.CO>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]2[CH3:1])[C:11](=[S:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=S
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=S
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 2'-deoxy-2'-methylthiocytidine (0.86 g, 3.15 mmol) in dry pyridine (20 ml) was added trimethylchlorosilane (2.0 ml, 15.75 mmol), and stirring continued for 15 min. Benzoyl chloride (2.18 ml, 18.9 mmol) was added to the solution followed by stirring for 2 hr. The mixture was then cooled in an ice-bath and MeOH (10 ml) was added. After 5 mins., NH4OH (20 ml, 30% aq.) was added and the mixture stirred for 30 min. The reaction mixture was then concentrated under vacuum and the residue purified by short silica gel (70 g) column chromatography. Elution with CH2Cl2 :MeOH (9:1, v/v), pooling of appropriate fractions and evaporation furnished the title compound (0.55 g, 46.6%) which crystallized from EtOH as needles, m.p. 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=[O:9])=[CH:4][CH:3]=1.[C:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1>[C:12]([C:20](=[CH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=CC(=O)c1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=CC(=O)c1ccc(Cl)cc1)C(=O)c1ccccc1

Procedure:
A solution containing 13.5 g of 4-chloro-phenylglyoxal and 15.4 g of ethyl benzoylacetate in 100 ml of anhydrous benzene was heated at the boiling temperature in the presence of a catalytic amount of piperidine (0.3 ml), till complete azeotropic distillation of the water formed during the reaction (about 6 hours).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH2:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)Cl>CC#N>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])#[N:5]
Reactant: CCCCCCNCCCCCC
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Reaction time: 40 h
Yield: 87.4 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (1.83 g, 10.0 mmol) in CH3CN (20 mL) were added K2CO3 (2.76 g, 20.0 mmol) and dihexylamine (1.85 g, 9.98 mmol) and the mixture was stirred at 80° C. for 40 h. The mixture was cooled to rt, poured into 100 mL of DCM and washed with water (100 mL×3), brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=125:2) to give the title compound as yellow oil (2.89 g, 87%).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[Mg].Cl[Si:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>O1CCCC1.C(OCC)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([Si:23]([CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)([CH3:24])[CH3:25])=[CH:27][CH:28]=1)[CH3:34]
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Reactant: Fc1ccc(CCCBr)cc1Oc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 10 °C

Procedure:
A small crystal of iodine was added to a mixture of 0.75 g (0.0024 mole) of 1-bromo-3-(4-fluoro-3-phenoxyphenyl)propane and 0.11 g (0.0045 mole) of magnesium powder in 1 ml of tetrahydrofuran. This mixture was heated in a water bath for about three hours. After heating, the clear solution was light grey-brown in color. The solution was cooled to 10° C., and 0.51 g (0.0022 mole) of chloro(4-ethoxyphenyl)dimethylsilane was added. This mixture was stirred for one-half hour and was then heated for an hour. Following dilution with diethyl ether, the reaction mixture was washed successively with 10% hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, leaving a colorless oil weighing 0.95 g as the residue. This oil was purified using a Chromatotron (eluant=ethyl acetate/hexane (2:98)), producing (4-ethoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a colorless oil. The proton and 13C nmr spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]1OC(O)C[O:35][CH:34]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH2:33][CH2:34][OH:35])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1COC(O)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C#N)c3)CCO)cc2)CC1
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and glycolaldehyde dimer (277 mg) in dichloromethane (20 ml) were added acetic acid (0.13 ml) and sodium cyanoborohydride (72 mg) in an ice bath. The mixture was stirred at the same temperature for 5 hours and then at room temperature for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/3 as an eluant to give the desired compound (1100 mg, yield 50%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[N:31]1([CH2:36][CH2:37][N:38]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:40]=[C:39]2[CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:50]3[CH2:49][CH2:48][CH:47]([C:39]4[N:38]([CH2:37][CH2:36][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[CH:42]=[C:41]([C:43]([F:45])([F:46])[F:44])[N:40]=4)[CH2:52][CH2:51]3)[C:3]=2[CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][C:9]1=[O:16]
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(Cl)ncnc32)c(OC)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(N4CCC(c5nc(C(F)(F)F)cn5CCN5CCCC5)CC4)ncnc32)c(OC)c1
Temperature: 220 °C

Procedure:
Combine 4-chloro-8-(2,4-dimethoxybenzyl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.65 g, 1.62 mmol), 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.76 g, 1.1 eq), N-methylpyrrolidinone (20 mL) and diisopropylethylamine (1.69 mL, 6.0 eq) in a sealed vessel. Heat at 220° C. for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromethane gradient, to give crude 8-(2,4-dimethoxybenzyl)-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (crude).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:29])[CH3:28].[BH4-].[Na+].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:11][CH:12]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:29][CH2:27][CH3:28])[CH:18]=2)[N:6]=1
Reactant: CCN
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 83 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (68 mg, 189 μmol) and THF (0.5 ml). To this was added a 2M solution of ethylamine in THF (100 μl). After stirring overnight methanol (1 ml) and sodium borohydride (11 mg) was added, then after another hour 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 61 mg (83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.1 Hz, 3H) 2.38-2.44 (m, 2H, partially obscured by solvent) 2.93 (s, 3H) 3.56 (s, 2H) 6.61 (br. s., 2H) 6.66 (br. s., 1H) 7.05 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.14-7.28 (m, 3H) 7.33-7.39 (m, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (APPI) m/z 389 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([OH:21])=O)[N:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([CH2:37][NH2:38])[OH:36]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([NH:38][CH2:37][CH2:35][OH:36])=[O:21])[N:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)O)n2)c1C
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)NCCO)n2)c1C

Procedure:
To the solution of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-acetic acid (85 g.), triethylamine (45 ml.), in anhydrous chloroform (750 ml.), cooled to -5° C., 35 ml. of ethyl chlorocarbonate and then 22 ml. of ethanolamine were added with stirring while the temperature was kept below +10° C. The reaction mixture was washed with water (350 ml.), and dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was washed with benzene (500 ml.) and crystallised several times from acetone. 55 g. of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-(N-β-hydroxyethyl)-acetamide were obtained, identical with the compound prepared as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:19][CH:18]=1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCOc1cc(C=O)cc(Br)c1OCc1ccc(C(=O)OC)cc1

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (4 g) with 4-bromomethylbenzoic acid methyl ester (3.73 g) was performed according to the method described in example 1a. Yield: 6.4 g. MS-ESI: [M+H]+=393/395
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:38])=[N:15][C:16]=3[NH:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:8]=[CH:7]1)C.[NH:40]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:21]([NH:20][C:16]2[N:15]=[C:14]([Cl:38])[N:13]=[C:12]3[C:17]=2[N:18]=[CH:19][N:11]3[C@@H:9]2[CH2:10][C@H:6]([N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH:7]=[CH:8]2)[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@H]2C=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.00 g, 3.64 mmol), di-t-butyl iminodicarboxylate (0.87 g, 4.00 mmol) and triphenylphosphine (0.14 g, 0.55 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 ml) is added followed by tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) and the mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 4:1). 1H nmr (CDCl3, 400 MHz); 8.20(s, 1H), 7.25(d, 4H), 6.85(d, 4H), 6.60(m, 1H), 6.35(m, 1H), 6.10(m, 1H), 5.80(m, 1H), 5.65(m, 1H), 5.35(m, 1H), 3.80(s, 6H), 3.15(m, 1H), 2.10(m, 1H), 1.55(s, 18H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(F)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)F)CN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Add acetic anhydride (0.084 mL, 0.91 mmol) to a solution of (2S,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2-fluoro-2-methylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.86 mmol) and triethylamine (0.81 mL, 130 mmol) in dry dichloromethane (10 mL) at room temperature and stir for 4 hours, concentrate and purify (silica gel cartridge chromatography, eluting with 2:1 to 1:2 hexanes:ethyl acetate), to give the desired compound as a white solid (0.37 g, 80%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][C:18]#[N:19])[CH2:12]1)=O)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[C:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)#[N:19]
Reactant: N#CCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CCC1CCCNC1
Reaction time: 2.5 h

Procedure:
1-Benzyloxycarbonyl-3-cyanomethylpiperidine (Method 22; 12.5 g) was dissolved in ethanol (20 ml) and ethereal HCl (1 ml) and 5% palladium on charcoal (2.0 g) was added. The mixture was shaken under an atmosphere of hydrogen for 2.5 hours. The catalst was filtered and the filtrate evaporated in vacuo. The crude product was dissolved in ethanol and recrystallized from ether. M/z 124 [M+].
Reaction SMILES: Cl.Cl.[C:3]([C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:29]C)=[C:13]([CH:28]=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)([C:7]#N)[CH3:6])#[N:4].I[CH:32]([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O>[CH:32]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:7])([CH3:6])[C:3]#[N:4])=[CH:28][CH:13]=1)([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: COc1ccc(C(C)(C#N)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1
Yield: 96.8 %

Procedure:
To a stirred solution of Compound 39 (500 mg, 3.10 mmol) and 2-Iodopropane (0.930 ml, 9.30 mmol) in acetone (8 ml) was added Cs2CO3 (4.55 g, 14.0 mmol), and refluxed for 2 h. The mixture was filtered over celite and washed with acetone. The filtrate was concentrated to give crude Compound 40. This was diluted with AcOEt, washed with water and brine, dried (MgSO4), and concentrated. This was purified by a column chromatography on silica gel to give Compound 40 (610 mg, 97%) as a colorless oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH:1]1([NH:6][C:9]([C:11]2[C:15]([NH:16][C:17]([C:19]3[C:24]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)=[CH:23][CH:22]=[C:21]([CH:32]4[CH2:34][CH2:33]4)[N:20]=3)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCCC2)n1
Yield: 19 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclopentylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (19%) as amorphous yellow solid.