Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:37][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)[N:23]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
14 mg (0.55 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 109 mg (0.50 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 143 mg (0.50 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed twice with water, and twice with heptane. The residue was dried at 40° C. in vacuum to give 191 mg (82%) of the title compound as white powder.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]([CH2:14][CH3:15])[C:11]([Cl:13])=[O:12])[CH3:9].[CH3:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[Cl:22]>C(Cl)(Cl)Cl>[ClH:13].[CH2:8]([N:10]([CH2:14][CH3:15])[C:11]([N:20]1[C:21]([Cl:22])=[C:17]([CH3:16])[N:18]=[CH:19]1)=[O:12])[CH3:9]
Reactant: CCN(CC)C(=O)Cl
Reactant: Cc1nc[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)n1cnc(C)c1Cl
Product: Cl
Reaction time: 2 h
Yield: 52.2 %

Procedure:
76 g of triethylamine and, thereafter, 68 g of diethylcarbamyl chloride were added dropwise to 58.5 g of 4-methyl-5-chloroimidazole in 200 ml of chloroform in a stirred flask provided with a thermometer and reflux condenser. Refluxing was then carried out for 2 hours, after which the mixture was cooled and the precipitated triethylamine hydrochloride was filtered off under suction. The filtrate was evaporated down under reduced pressure, 500 ml of acetone was added to the residue, and HCl gas was passed in while the mixture was cooled with ice. The resulting precipitate was filtered off under suction and dried to give 66 g (52.4%) of 1-N-diethylcarbamyl-4-methyl-5-chloroimidazole hydrochloride; mp. from 208° C., with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH2:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH:19][C:30]([C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=3)=[N:27][CH:28]=2)=[O:31])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cc(CCN)cc(OC)c1
Product: CCOC(=O)C(C)(C)Oc1cc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(OC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14](O)=[O:15])[N:9]=1>C(Cl)Cl>[ClH:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14]([Cl:2])=[O:15])[N:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: ClCCl
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Product: Cl
Temperature: -20 °C

Procedure:
To a solution of 218 mg of phosphorus pentachloride in 3 ml of methylene chloride, 202 mg of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid is added under cooling at -20° C. with stirring and the mixture is stirred for half an hour at -20° C. and for two hours at -5° C. The reaction mixture in concentrated under reduced pressure and the residue is triturated with 10 ml of hexane. The precipitate is collected by filtration to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1([CH3:19])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[O:8]1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O>[CH3:6][C:7]1([CH3:19])[C:11]([CH3:12])([CH3:13])[O:10][B:9]([C:14]2[CH:18]=[N:17][N:16]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:15]=2)[O:8]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (Yield: 46%)
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C=CCCCCCC.CCCCCCC=CCCCCCC.[C:40](OCCCCCCCCC=C)(=[O:42])[CH3:41]>>[C:40]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:42])[CH3:41]
Reactant: C=CCCCCCCCCOC(C)=O
Reactant: CCCCCCC=CCCCCCCCCO
Agent: CCCCCCC=CCCCCCC
Solvent: C=CCCCCCC
Product: CCCCCCC=CCCCCCCCCOC(C)=O

Procedure:
A process for preparing 9-hexadecenyl alcohol by reacting 1-octene or 7-tetradecene with 9-decenyl acetate in accordance with the method of claim 7 to obtain 9-hexadecenyl acetate and then reacting the acetate with water to obtain the corresponding alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH2:32]([NH2:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH2:32]([NH:34][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=1)=[O:9])[CH3:33]
Reactant: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
0.43 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphine (1.12 mmol) was added to 0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid (79) (1.12 mmol) prepared in Example 66 dissolved in 1.0 mL of tetrahydrofuran and 1.0 mL of dimethylformamide, and stirred at room temperature for 10 minutes. 0.56 mL of ethylamine (1.12 mmol) in 2.0 M tetrahydrofuran solution was added thereto, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. Then, the mixture was dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.35 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid ethyl amide (yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.C[O:13][C:14](=[O:21])[C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH2:16].[CH2:22]1COCC1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:16][C:15]([C:14]([OH:13])=[O:21])([CH2:17][C:18]([O:20][CH3:22])=[O:19])[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: C=C(CC(=O)O)C(=O)OC
Reactant: C1CCOC1
Reactant: COc1ccc(C=NO)cc1
Product: COC(=O)CC1(C(=O)O)CC(c2ccc(OC)cc2)=NO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
4-Methoxybenzaldehyde oxime (5.00 g, 33.1 mmol) and itaconic acid monomethyl ester (5.72 g, 39.7 mol) were added together with 200 mL of THF. To the above mixture was added bleach (84 mL of 0.67M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N2 for 12 h. The THF was removed in vacuo. The aqueous mixture was acidified with aqueous HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated, and chromatographed with 10-30% MeOH in CH2Cl2 on silica gel to give 5.58 g of the desired product (58%). 1H NMR (DMSO-d6): δ 3.08 (m, 2H); 3.61 (s, 3H); 3.55-3.87 (m, 2H); 3.80 (s, 3H); 7.00 (d, 2H); 7.61 (d, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].S(O[CH2:30][CH2:31][Cl:32])(C1C=CC(C)=CC=1)(=O)=O>O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:30][CH2:31][Cl:32])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Solvent: O
Product: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12
Reaction time: 2 h

Procedure:
A solution of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran in 15 ml of a 50% aqueous solution of soda was brought to 90° C. and 21 g (0.1 mole) of 2-chloro ethanol tosylate was slowly added, it was kept at 90° C. for 2 hours, diluted in 1 l of water, filtered and recrystallized in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)O)cc1I
Temperature: 0 °C
Reaction time: 14 h

Procedure:
3-Fluoro-4-methylbenzoic acid (1 g, 6.48 mmol, 1 eq) was dissolved in trifluoromethanesulphonic acid (10 ml) and the reaction was cooled to 0° C. To the above solution N-iodosuccinimide (1.46 g, 6.48 mmol, 1 eq) was added in portion and the reaction was stirred at room temperature for 14 h. Later the above solution was poured into 50 ml of ice water, the solid obtained was filtered. The solid was dissolved in ethylacetate, washed with sodiumthiosulphate solution and brine, the organic layer was concentrated to get the desired product as light brown solid. Yield: 1.5 g (83%). 1H NMR (400 MHz, CDCl3): δ 2.35 (s, 3H), 7.68 (d, 1H, J=8 Hz), 8.14 (s, 1H). 13.50 (br, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([OH:19])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@:15]1([CH3:20])[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14]1.[OH:19][C@@:15]1([CH3:20])[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14]1
Reactant: CC1(O)CCCC(N)C1
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2CCC[C@](C)(O)C2)n1
Product: CSc1ncc(C#N)c(N[C@H]2CCC[C@@](C)(O)C2)n1
Temperature: 100 °C
Yield: 33 %
Yield: 34 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (3.71 g, 20 mmol)), 3-amino-1-methylcyclohexanol (3.0 g, crude), DIEA (3.23 g, 25 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. The organic solvents were removed under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum) to afford the cis-isomer (0.90 g, 3.24 mmol, 17% yield over 3 steps) and trans-isomer (1.80 g, 6.47 mmol, 34% yield over 3 steps). The cis-isomer (0.90 g, 3.24 mmol) was separated by chiral SFC (Column IF; method: 70-30-CO2-MeOH; CO2 Flow Rate: 2.1; Col. Temp.=40° C.) to give 4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 1: 300 mg, 1.08 mmol, 33% yield, 100% e.e.) and 4-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 2: 310 mg, 1.12 mmol, 34% yield, 100% e.e.), MS (ESI) m/z 279.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])=[O:5].S(Cl)(Cl)=O.O.[C:24](=O)([O-])O.[Na+]>CO>[CH3:24][O:9][C:8](=[O:10])[C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:18])[CH2:11][CH:12]=[CH2:13]
Reactant: O=C([O-])O
Reactant: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CO
Product: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of 2N aqueous sodium hydroxide solution (27.4 ml) and THF (55 ml), L-allylglycine (5.22 g) was dissolved, and 2,6-dichlorobenzoyl chloride (7.79 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. After concentrating the reaction solution to remove methanol, water (100 ml) was added thereto and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.65 g). NMR (H1, CDCl3): δ 2.66-2.73 (1H, m), 2.80-2.86 (1H, m), 4.99 (1H, td, J=7.6, 5.6 Hz), 5.18-5.25 (2H, m), 5.76-5.86 (1H, m), 6.39 (1H, brd, J=7.6 Hz), 7.25-7.34 (3H, m) (2) Under an argon atmosphere, a solution of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.46 g) in methanol (120 ml) was cooled to 0° C. Thionyl chloride (5.22 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (11.68 g). NMR (H1, CDCl3): δ 2.62-2.69 (1H, m), 2.76-2.83 (1H, m), 3.79 (3H, s), 4.96 (1H, td, J=7.8, 5.4 Hz), 5.14-5.21 (2H, m), 5.72-5.82 (1H, m), 6.42 (111, brd, J=6.8 Hz), 7.25-7.34 (3H, m)
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+].CCN(C(C)C)C(C)C.Br[CH2:48][CH2:49][O:50][CH3:51]>C(Cl)Cl>[CH3:51][O:50][CH2:49][CH2:48][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (200 mg, 0.45 mmol, 1.00 equiv) in DCM (10 mL) was added hydrogen chloride (conc., 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, extracted with DCM (40 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in DMF (5 mL) and DIEA (333 mg, 2.58 mmol, 6.00 equiv) and 1-bromo-2-methoxyethane (598 mg, 4.30 mmol, 10.00 equiv) were added. Stirring was continued for 2 h at 65° C. The mixture was diluted with DCM (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 43.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to give the desired 2-[(3R)-12-([4-[(2-methoxyethyl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide (50 mg) as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 5.32-5.23 (m, 2H), 3.91-3.83 (m, 1H), 3.52 (t, 2H, J=5.1 Hz), 3.38 (s, 3H), 3.19-2.98 (m, 3H), 2.91-2.71 (m, 3H), 2.69-2.55 (m, 1H), 2.39-2.21 (m, 4H), 2.11-2.01 (m, 2H), 1.72-1.23 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution 2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenol (900 mg, 2.5 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (1.62 g, 4.9 mmol, 2 eq). The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (540 mg, 2.9 mmol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for 30 min, then water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc 20:1 to 5:1) to give the title compound (300 mg, 26%).
Reaction SMILES: C(O[C:4](=O)[N:5]([CH2:7][C:8]1[C:9]([CH:24]2[CH2:26][CH2:25]2)=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)C)C.[OH-].[K+].O.NN.CCOC(C)=O>C(O)CO>[CH:24]1([C:9]2[C:8]([CH2:7][NH:5][CH3:4])=[CH:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:10]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)N(C)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: O
Product: CNCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 210 °C
Yield: 87.3 %

Procedure:
0.83 g (2.2 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamic acid ethyl ester was dissolved in 15 ml of ethylene glycol. Then, 1.72 g (26.4 mmol) of potassium hydroxide (86%) and 0.44 ml=0.46 g (9.0 mmol) of hydrazine hydrate were added and the reaction mixture heated up to 190° C. (oil bath, 210° C.) for 90 minutes. After cooling down below 80° C., some pieces of ice were added to the reaction mixture followed by EtOAc. It was then extracted twice with EtOAc; the combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of MeCl2, MeOH) to give 0.59 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>ClCCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 83 °C
Reaction time: 16 h

Procedure:
A suspension of 2,6-dichloropurine (22.0 g, 116.4 mmol), dihydropyran (11.5 mL, 126 mmol) and D-(+)-10-camphorsulfonic acid (2.20 g, 9.47 mmol) in 1,2-dichloroethane (300 mL) was stirred at 83° C. for 16 hours. The initially white suspension, after 2 hrs, turned yellow and then black. The reaction mixture was diluted with CCl3H and then washed with brine. The organic layer is dried over MgSO4, filtered, concentrated and triturated with hexane 3 times to give the desired product. 1HNMR (300 MHz, CCl3D): δ 8.33 (s, 1H), 5.75 (dd, J=10.4 Hz, 2.5 Hz, 1H), 4.18 (m, 2H), 3.79 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH2:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][NH:23][CH2:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Solvent: O
Product: OC1(CNCCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.2 g (95 mmol) of 5-benzyl-1-oxa-5-azaspiro[2,4]heptane are added dropwise to 15.6 ml (0.115 mol) of benzylmethylamine in 300 ml of water and the mixture is stirred for 15 hours at room temperature. The product is extracted using CH2Cl2, the extracts are dried using K2CO3 and concentrated, and incipient distillation is carried out up to 160° C. (oil bath temperature).