Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH3:21])[CH:9]=2)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[W]>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][Br:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(C)cc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Yield: 36.6 %

Procedure:
6-Methyl-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (3 g, 10.3 mmol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (2 g, 11.4 mmol) and 2,2′-azobisisobutyronitrile (500 mg, 3.09 mmol) were added thereto. Then, the mixture was refluxed for 3 hours under a 375 W tungsten lamp. After the reaction is completed, the organic layer was extracted with dichloromethane/saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 6-bromomethyl-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (1.4 g, yield 36.7%) as yellow oil.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:19]=[C:18]([CH3:20])[C:11]([O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])=[C:10]([CH3:21])[CH:9]=2)=[CH:4][N:3]=1.NC1N=CC(C2C=C(C)C(OCC(OC)=O)=C(C)C=2)=CN=1.O.NN>CCO>[CH3:20][C:18]1[CH:19]=[C:8]([C:5]2[CH:6]=[N:7][CH:2]=[N:3][CH:4]=2)[CH:9]=[C:10]([CH3:21])[C:11]=1[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15]
Reactant: Cc1cc(-c2cnc(N)nc2)cc(C)c1OCC(=O)NN
Agent: COC(=O)COc1c(C)cc(-c2cnc(N)nc2)cc1C
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cncnc2)cc(C)c1OCC(=O)NN
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Synthesis of 2-(4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenoxy)acetohydrazide: methyl 2-(4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenoxy)acetate (0.28 g, 1 mmol) was dissolved in EtOH. Hydrazine monohydrate (0.06 g, 1.2 mmol) was added thereto, followed by stirring at 100° C. for 8 hours under reflux. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The formed solid was filtered to obtained 2-(2,6-dimethyl-4-(pyrimidin-5-yl)phenoxy)acetohydrazide (0.31 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:6]=[C:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=4)=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)cc(C)n1
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: C1COCCO1
Product: Cc1cc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)cc(C)n1

Procedure:
To a solution of intermediate 20 (1.066 mmol) in 1,4-dioxane (4.5 ml) and a saturated solution of NaHCO3 (4.5 ml) was added intermediate 5 (0.23 g, 0.906 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.12 mg, 0.106 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 50% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 9 that was precipitated from diethylether (0.144 g, 42%).
Reaction SMILES: [N:1]1([CH:7](O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>C1COCC1.C(OCC)C>[N:1]1([CH2:7][CH2:8][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)N1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.83 h
Yield: 34.3 %

Procedure:
A 1 L 3-neck round bottom flask was charged with anhydrous THF (200 mL), 1-piperidinylethanol (14.9 g, 15.27 mL, 0.115 mol), 4-hydroxybenzaldehyde (14.16 g, 0.116 mol), and triphenylphosphine (31,21 g, 0.119 mol) under a nitrogen atmosphere. The above mixture was stirred and diethylazodicarboxylate (DEAD; 22.6 g, 20.4 mL, 0.130 mol) in anhydrous THF (25 mL) was added dropwise over 15 min during which time the temperature was carefully monitored and not allowed to exceed 60° C. The reaction was stirred overnight at ambient temperature and then worked up by the addition of 10 mL 30% hydrogen peroxide and extraction of by ethyl ether. The organic layer was washed eight times with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was purified by chromatography over silica gel using a Waters LC2000 instrument. The elution solvent employed a gradient system beginning with 100% methylene chloride and ramping to 9:1 methylene chloride:methanol over 50 min at a flow rate of 150 mL/min. Concentration of appropriate fractions provided 9.2 g (35%) of the desired product as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Br:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>O>[Br:26][CH:27]([CH3:31])[C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:13])=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])=[O:29]
Reactant: Cc1ccc(C)c(NCC=O)c1C
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)c(N(CC=O)C(=O)C(C)Br)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2,3,6-trimethylanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-bromopropionyl cloride (0.11 mole) is incrementally added with stirring. After addition is is competed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-bromopropionyl-2,3,6-trimethylanilino)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 148.5 %

Procedure:
A mixture of 6-(3-chloro-2-thienyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g), aminoguanidine hydrochloride (0.6 g), concentrated hydrochloric acid (1.1 ml), water (1.1 ml) and ethanol (50 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol to give 6-(3-chloro-2-thienyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 119) (1.2 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20](C)[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCCC1.NC1SC=NC=1.C([O:51][C:52](=[O:56])C(S)C)C>>[CH:17]1([N:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:52]([OH:56])=[O:51])=[CH:9][N:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCOC(=O)C(C)S
Agent: C[C@H]1CC[C@H](NC2CCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCC2)s1

Procedure:
{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclopentyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:20]([C:19]1[CH:18]=[C:17]([CH:30]=[CH:29][CH:28]=1)[O:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(COc3cccc(C(=O)c4ccccc4)c3)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
Methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (2.478 g, 9.207 mmol) was added to a mixture of 3-hydroxybenzophenone (2.19 g, 11.05 mmol) and potassium carbonate (3.054 g, 22.10 mmol) in dimethyl formamide (46 mL). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with 10% aqueous potassium carbonate (×5), 2M NaOH (×5), brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (3.721 g, quantitative yield). The material was used directly in the next step with no further purification.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][OH:16].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:5]1([CH2:4][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH2:15][OH:16])[CH2:3][CH2:2]1
Reactant: OCc1nc2ccccc2[nH]1
Reactant: BrCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCc1nc2ccccc2n1CC1CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 25.8 %

Procedure:
To a solution of (bromomethyl)cyclopropane (0.39 mL, 4.02 mmol) and (1H-benzoimidazol-2-yl)-methanol (596 mg, 4.02 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (0.84 mL, 4.82 mmol). The reaction mixture was stirred at 60° C. for 3 days. Then it was cooled to room temperature and quenched with saturated NaHCO3 (15 mL) and the phases were separated. The aqueous phase was washed with CH2Cl2 (3×20 mL). Then the combined organic layers were washed with brine (2×30 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow solid (210 mg, 26%). 1H NMR (CDCl3) δ 0.40-0.45 (m, 2H), 0.52-0.61 (m, 2H), 1.22-1.33 (m, 1H), 4.13 (d, 2H, J=6.6 Hz), 4.88 (s, 2H), 7.22-7.24 (m, 2H), 7.36-7.38 (m, 1H), 7.66-7.69 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 69.7 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 99%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 18.3 g (0.112 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 26.4 g of the target compound was obtained as a pale yellow solid (yield: 57%, purity: 82%, pure content: 21.6 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[C:23]([CH3:29])[NH:24]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:23]1[NH:24][C:25]2[C:21]([N:22]=1)=[C:20]([NH:18][C@H:16]([C:8]1[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=1)[CH3:17])[N:28]=[CH:27][N:26]=2
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Cc1nc2c(Cl)ncnc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc2c(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)ncnc2[nH]1
Yield: 32.7 %

Procedure:
A solution of (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (150 mg, 0.62 mmol, 1.00 equiv, 98%), 6-chloro-8-methyl-9H-purine (150 mg, 0.87 mmol, 1.41 equiv) and ethylbis(propan-2-yl)amine (0.3 mL, 98%) in butan-1-ol (6 mL) was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The residue was purified on a C18 column eluted with water/acetonitrile to give 75 mg (30%) of 158 as a white solid. LC-MS (ES, m/z) 370 [M+H]+. H-NMR (300 MHz CD3OD, ppm) δ 8.04 (s, 1H), 7.69 (d, 1H), 7.55 (m, 5H), 7.30 (m, 2H), 7.11 (d, 1H), 5.63 (s, 1H), 2.55 (s, 3H), 1.71 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=O.S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][Cl:15]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: O=S(Cl)Cl
Product: Fc1cc(CCl)c(Cl)nc1Cl
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
2,6-Dichloro-5-fluoronicotinic acid (2) (14 g) was dissolved in thionyl chloride (70 mL). The mixture was heated at 85° C. with stirring for 2.5 h and the thionyl chloride was removed under reduced pressure, yielding a yellowish oil, 2,6-dichloro-5-fluoronicotinyl chloride (3). Monoethyl malonate (27 g) and 6 mg of biquinoline was dissolved in 560 mL of dry THF and cooled to −30° C. A solution of 2.5 M of n-butyllithium in hexane was added until a pink color remained at −5° C. (160 mL). The suspension was then cooled to −50° C. The acid chloride obtained as described above, dissolved in 50 mL THF was then added to the suspension dropwise with stirring. The dry ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was acidified with 400 mL of 1N HCl and was extracted with ether. It was washed with aqueous sodium bicarbonate solution and water. The ether solution was dried, evaporated to dryness and washed with hexane to give 27 g of (4). m.p=63-66° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:11]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12]2>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:15]2[OH:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1CC2OC2C1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O[C@H]1CCC[C@@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A flask was charged with (3,5-difluorophenyl)magnesium bromide (149 mL, 149 mmol) and copper (I) iodide (1.901 g, 9.98 mmol). To this reaction mixture, 6-oxabicyclo[3.1.0]hexane (12.53 g, 149 mmol) dissolved in THF (25 mL) was added dropwise. The reaction mixture warmed upon the addition of the epoxide. The reaction was stirred at rt for 2 h at rt. The reaction mixture was quenched by the addition of a solution of ammonium chloride. Ether was added and the organic layer was collected, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to afford (1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (26.5 g, 134 mmol, 90% yield).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36].[CH2:41](I)[CH3:42]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:41][CH3:42])[C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCI
Reactant: CCCC(CCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)OC(=O)N(CC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 1-propylbutyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 75%)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:45])[C@@H:41](O)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:45])[C@@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Agent: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyric acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide, no further purification was undertaken. LCMS: RT=4.05 min, [M+H]+=494
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([NH:16][C:10]1[C:5]2[S:4][CH:3]=[C:2]([Br:1])[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(Br)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To 5 ml of a solution of 426 mg (1.5 mmol) of 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine in DMF was added 188 mg (3.3 mmol) of allylamine under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 1 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 359 mg (yield: 78.6%) of the title compound.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=O)[CH2:3][CH2:2]2.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[N:1]12[CH2:9][C@H:5]([CH2:6][CH2:7][CH2:8]1)[C@H:4]([C:20]#[N:21])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC1C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#C[C@@H]1CCN2CCC[C@H]1C2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of 2.00 g of 1-azabicyclo[3.3.1]nonan-4-one in 100 ml of dimethoxyethane, 3.65 g of p-toluenesulfonylmethylisocyanide and 1.13 g of ethanol were added, followed by cooling to 5° C. Then, 4.00 g of potassium tert-butoxide was added while keeping the internal temperature below 10° C. The mixture was stirred at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The precipitate thus formed was removed by filtration. The residue obtained by evaporation of the solvent was purified by an alumina column chromatography (eluent: chloroform:hexane=1:1). The resulting crude product was then purified by silica gel column chromatography (eluent: chloroform:methanol=20:1), whereby 1.01 g of (4R*,5R*)-1-azabicyclo[3.3.1]nonane-4-carbonitrile was obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].CO[C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH:12]=1.Cl>CO>[OH:3][NH:2][C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:28][CH:29]=2)[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:13][CH:12]=1
Reactant: NO
Reactant: COC(=O)CCc1cnc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NO)s2)cc1
Temperature: 90 °C
Yield: 21.8 %

Procedure:
Hydroxylamine hydrochloride (6.96 g) was suspended in methanol ( 35 mL) and heated to 90° C. This solution was added to potassium hydroxide (8.34 g) dissolved in methanol (21 mL) After 15 minutes of stirring, the solution was filtered and 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]propionic acid methyl ester (0.80 g, 1.53 mmol) was added. The reaction was stirred at room temperature for 15 minutes, 1N HCl (50 mL) was added, and the methanol was removed in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (1N). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The title compound (0.175 g, 17%) was isolated by crystallization from a mixture of ethyl acetate and methanol. MS [M+1] 524.1.