Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].O1CCOCC1.O>CCOC(C)=O>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:18]1[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH:11]=[CH:10]2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reaction time: 1 h

Procedure:
Followed Scheme 3 starting from 2-chloroquinolin-6-ol (Intermediate 2) and 4-cyanophenylboronic acid, and using 1,4-Dioxane:H2O solution. Reaction was run at 100° C. in a microwave reactor for 1 hour. Ethyl acetate workup was followed by column chromatography (5% to 50% EtOAc in hexanes gradient).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16]([O:18]N2C(=O)CCC2=O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)C=CC=CC=1.[Al]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:18])[N:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:37][C:36]2[CH:35]=[CH:34][CH:33]=[CH:40][CH:39]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)ON1C(=O)CCC1=O
Agent: [Al]
Solvent: ClCCl
Product: O=C(Cn1cccc(OCc2ccccc2)c1=O)N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
15 (0.5 g, 1.4 mmol) was dissolved in 50 mL of dry CH2Cl2. 4-phenylbenzylamine (0.28 g, 1.5 mmol) was dissolved in 10 mL of dry CH2Cl2 to yield an almost clear, colorless solution and was quickly added to the stirring solution of 15. The reaction flask was protected from light with aluminum foil and stirred at room temperature under a dinitrogen atmosphere for 18 h. A white solid was removed by vacuum filtration. A second crop of white precipitate was isolated after cooling the filtrate at 4° C. for 3 h. The CH2Cl2 filtrate layer was washed with 0.05 M aqueous sodium bicarbonate solution (3×25 mL). The methylene chloride layer was washed with ddH2O (1×25 mL) and then dried over anhydrous sodium sulfate. The clear, colorless solution was concentrated by rotary evaporation to yield a white solid. Yield: 55%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.33 (d, J=6.0 Hz, 2H, —CH2—), 4.61 (s, 2H, —CH2—), 5.00 (s, 2H, —CH2—), 6.12 (t, J=7.2 Hz, 1H, Ar—H), 6.91 (d, J=7.6 Hz, 1H, Ar—H), 7.22 (d, J=6.8 Hz, 1H, Ar—H), 7.39 (m, 9H, Phenyl-H, Bz—H), 7.62 (m, 5H, Bz—H), 8.70 (t, J=5.8 Hz, 1H, —NH—).
Reaction SMILES: [Cl:1][C:2]1([C:5]2OC(=O)[S:7][N:6]=2)[CH2:4][CH2:3]1.[S:11]([C:21]#[N:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1([C:5]2[N:22]=[C:21]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[S:7][N:6]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=c1oc(C2(Cl)CC2)ns1
Solvent: CCCCC
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(C3(Cl)CC3)ns2)cc1
Yield: 85.4 %

Procedure:
66.2 g (372 mmol) of 5-(1-chlorocyclopropyl)-1,3,4-oxathiazol-2-one and 70.9 g (391 mmol) of tosyl cyanide are stirred in 125 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and treated with pentane, and the precipitate is filtered off and dried under vacuum. 100.0 g of product are obtained (99.9% purity, 85.2% yield, log P (pH 2.3)=3.67).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH:30][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH:25]=1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1cc(CN)no1
Product: Cc1cc(CNC(=O)c2cccn2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)no1
Yield: 65 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (750 mg, 2.41 mmol) and (5-methylisoxazol-3-yl)methanamine bromhydrate (698 mg, 3.62 mmol) following the experimental procedure described in Preparation 27a. 613 mg (63% yield) of the desired compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2[nH]ccc2c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4[nH]ccc4c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide 5-fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.13 (s, 1H), 10.25 (bs, 1H), 9.87 (bs, 1H), 9.43 (bs, 1H), 8.16 (d, 1H, J=5.1 Hz), 7.89 (d, 1H, J=0.09 Hz), 7.39-7.27 (m, 3H), 7.03-6.94 (m, 2H), 6.83 (s, 1H), 6.48 (d, 1H, J=7.5 Hz), 6.40 (t, 1H, J=2.1 Hz); LCMS: purity: 92%; MS (m/e): 336(MH+).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.O.Cl>CN(C)C=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][N:22]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:23]=1
Reactant: CSc1nc2ccccc2c(=O)[nH]1
Reactant: COCCOc1cn[nH]c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 58.5 %

Procedure:
96 g (0.5 mole) of 2-methylthio-4(3H)-quinazolinone are stirred in 250 ml of dimethylformamide with 142 g (1 mole) of 4-(β-methoxy-ethoxy)pyrazole at the reflux temperature for 40 hours. After cooling, 2.5 litres of water are added and a pH value of 3 is established with hydrochloric acid. The crude product which separates out (97.3 g of melting point 119°-24°) is recrystallized from isopropanol. 83.8 g of 2-(4-β-methoxyethoxy-1H-pyrazol-1-yl)-4(3H)-quinazolinone of melting point 125° to 127° C. are obtained.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9](I)[C:8]=1[OH:15]>C(O)(=O)C>[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[OH:15]
Reactant: Oc1c(F)cc(I)cc1I
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)cc(F)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrate (4.3 g) was added in portions over 1 hour to a solution of 2-fluoro-4,6-diiodophenol (16.3 g) in acetic acid (100 ml). The mixture was stirred for a further 15 minutes and was then poured into ice water (250 ml). The aqueous solution was concentrated under reduced pressure, extracted with chloroform and the organic solvent removed under reduced pressure. The residue was steam distilled to give 2-fluoro-4-iodo-6-nitrophenol which crystallised from aqueous ethanol (1.8 g) m.p. 96°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[CH3:11]S(C)=O.CI>O>[CH3:11][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CS(C)=O
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1ccccn1
Temperature: 25 °C

Procedure:
Also, 2-(methoxymethyl)pyridine is prepared by the following alternative procedure. A mixture of 10.9 g. of 2-pyridinemethanol and 2.4 g. of sodium hydride in 50 ml. of dimethylsulfoxide is warmed on a steam bath for 15 minutes, then cooled to room temperature. Methyl iodide (14.2 g.) is added then the mixture is heated at 40°C. for one hour. Water (150 ml.) is then added and the mixture is extracted with ether. The extracts are dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C@H:10]2[C@@H:14]([C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)C(=O)[N:11]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[C:44](=[O:47])([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH2:24]([N:13]1[C:14]2=[C:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:9][C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]2[N:11]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:44]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cc1ccccc1)[C@@H]1[C@H](C(=O)Cc2ccccc2)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1n(Cc2ccccc2)c2c(Cc3ccccc3)oc(Cc3ccccc3)c2n1Cc1ccccc1
Yield: 76 %

Procedure:
A solution of (4R-cis)-4,5-bis(phenylacetyl)-1,3-bis(benzyl)-2-imidazolidinone (79 mg, 0.16 mmol) and ammonium acetate (25 mg, 0.32 mmol) in acetic acid (2 ml) was refluxed 18 hours. The solution was neutralized with solid potassium carbonate and partitioned between EtOAc/water. The aqueous phase was washed twice with EtOAc. All organic extracts were combined and dried over MgSO4, then concentrated to a brown oil. Further purification was achieved by preparative TLC (silica gel, 30% EtOAc/hexane) to give the product as a yellow-brown oil, (59 mg, 76% yield). 1HNMR (CDCl3) δ7.10-7.44 (m, 10H), 4.99-5.16 (m, 2H) , 4.17-4.29 (m, 3H), 3.59 (d, 1H), 2.54 (m, 1H), 2.07-2.33 (m, 3H), 1.21-1.50 (m, 6H), 0.84-0.93 (m, 6H). MS: 417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2(Br)[CH2:11][C:10]2(Br)Br)=[CH:4][CH:3]=1.C[Li].O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH2:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2(Br)CC2(Br)Br)cc1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(CC2=CC2)cc1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 1.20 g (0.00298 mol) of 2-(4-chlorophenylmethyl)-1,1,2-tribromocyclopropane in 6 ml of diethyl ether was placed under a nitrogen atmosphere via use of a Firestone valve. While cooling in an ice water bath, 6.38 ml (0.00893 mol) of 1.4M methyl lithium in diethyl ether was added slowly by syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.430 g of 1-(4-chlorophenylmethyl)-cyclopropene as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.B(Br)(Br)Br.[NH4+].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C(O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a cooled (−78° C.) solution of 5-methoxy-benzofuran-2-carboxylic acid (5.0 g, 26.0 mmol) in DCM (100 mL) was added BBr3 (7.4 mL, 19.5 g, 78.0 mmol) and the reaction mixture was stirred (2 h). The reaction mixture was warmed (rt) and subsequently cooled (0° C.) and treated with saturated NH4Cl (100 mL). The resultant biphasic mixture was partitioned and the aqueous layer was extracted with EtOAc (3×100 mL), dried, filtered and concentrated in vacuo to afford the title compound (4.6 g, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][C:26](N4C=CN=C4)=[O:27])=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1>ClCCl>[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:8][CH2:9][CH2:10]1
Reactant: C1CCNCC1
Reactant: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)n1ccnc1
Solvent: ClCCl
Product: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)N1CCCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Piperidine (0.1 ml, 1.1 mmol) was added to a stirred solution of 3-cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine (E167, Step 1) (150 mg, 0.42 mmol) in dichloromethane (5 ml). After stirring at room temperature for 5 days the reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E167); MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].CI.CCCCCC>C1COCC1.O.C(OCC)(=O)C>[CH3:1][N:9]1[C:10]([Br:16])=[C:11]([Br:15])[C:12]([C:13]#[N:14])=[C:8]1[Br:7]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(Br)c(Br)c(C#N)c1Br
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 0.87 g (7.75 mmol) of potassium t-butoxide in 30 mL of dry THF under a nitrogen atmosphere is added dropwise from an addition funnel 2.10 g (6.39 mmol) of 2,4,5-tribromopyrrole-3-carbonitrile in 20 mL of dry THF. After 15 minutes, 0.64 mL (10.3 mmol) of methyl iodide is added by syringe over 2 minutes. After several hours at room temperature, the mixture is diluted with 100 mL of water and 75 mL of ethyl acetate. The separated water phase is extracted again with ethyl acetate and the combined organic layers are washed with dilute sodium hydroxide, water, and saturated salt solution. After drying over magnesium sulfate, the mixture is shaken with activated charcoal and filtered. Concentration in vacuo gives a white solid which is slurried with hexane and recrystallized from ethyl acetate to afford the title compound as a white solid, mp 151°-152° C.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3].[CH3:19]I.[H-].[Na+].O>CN(C)C=O>[CH3:19][O:1][C:2]([CH:5]1[CH2:9][O:8][C:7]([CH3:10])([CH3:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(C(C)(C)O)COC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)C1COC(C)(C)N1C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
tert-Butyl 4-(1-hydroxy-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Y. Yonezaw et al., Synthesis, 634-636 (2000); 2.6 g) and methyl iodide (1.2 ml) were dissolved in dimethylformamide (20 ml). Sodium hydride (0.59 g) and n-tetrabutyl iodide ammonium (0.72 g) were added thereto at 0° C., and mixed at room temperature for 2.5 days. To the reaction mixture was added water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (2.5 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11]C)=[O:10])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>COCCOC.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Pd(dppf)Cl2 (0.214 g, 0.02 mmol) was added to a mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (2.07 g, 10 mmol) and 4-(trifluoromethyl)phenyl-boronic acid (1.90 g, 10 mmol) in DME (100 mL) and sat. aq. NaHCO3 (20 mL), and the mixture was stirred in an atmosphere of argon at 80° C. for 3 h. The reaction mixture was cooled to 20° C. and added to ice water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was extracted with saturated sodium carbonate solution (50 mL). The combined aqueous layers were acidified by the addition of 25% HCl (100 mL) and subsequently extracted with ethyl acetate (2×100 mL). The organic phase was washed with brine, dried over sodium sulfate, and the solvents were removed under reduced pressure. The residual solid was recrystallized from ethyl acetate/heptane to give the title compound (1.82 g, 60%) as light red solid. MS ISN (m/e): 301.2 [(M−H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.51 (s, 1H), 8.33 and 7.84 (2 d, 2×2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH2:9]([NH:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cncc(NCc2ccccc2)n1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.31 g, 8.8 mmol), benzylamine (1.15 g, 10.7 mmol) and K2CO3 (1.65 g, 11.9 mmol) in acetonitrile (6 mL) was heated at 85° C. for 13 h in a sealed pyrex flask. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The yellow solid residue was dissolved in a small volume of methanol and purified by silica gel chromatography (18×4 cm) using CHCl3/MeOH (98:2) as eluent. A second purification (SiO2; 16×4 cm) using CHCl3 as eluent furnished 1.55 g (81%) of the title compound as a light yellow solid. HRMS m/z calcd for C11H10ClN3 (M)+ 219.0563, found 219.0568. Anal. (C11H10ClN3) C, H, N.
Reaction SMILES: [CH:1]1([C@H:7]([OH:10])[C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O.CCCCCC>[Si:20]([O:10][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]#[CH:9])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H](O)C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-cyclohexylprop-1-yn-3-ol, prepared as shown in Preparation 3 or 4, (2.76 g, 0.02 mol), in 10 ml N,N dimethylformamide (DMF), cooled to 0° C., was added imidazole (2.1 g), followed by tert-butyldimethylchlorosilane (3.1 g, 0.02 mol). The mixture was stirred for 3 h. Water (80 ml) and hexane (80 ml) were added; the organic layer was separated and combined with 2×80 ml of hexane extractions of the aqueous layer. The solvent was removed (in vacuo), after drying over sodium sulfate, to give a crude residue (4.3 g) which was chromatographed on silica gel (80 g), eluting with ethyl acetate-hexane (2:1, v/v) to afford (S)-3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-yne.
Reaction SMILES: NC(N)=[S:3].Cl[C:6]1[N:7]2[C:11]([N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)=[N:10][CH:9]=[N:8]2>C(O)C>[SH:3][C:6]1[N:7]2[C:11]([N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)=[N:10][CH:9]=[N:8]2
Reactant: CC(C)(C)c1cc(Cl)n2ncnc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)(C)c1cc(S)n2ncnc2n1

Procedure:
8.7 g of thiourea was dissolved in 150 ml of ethanol and thereto was added 4-chloro-6-t-butyl-1,3,3a,7-tetraazaindene. The resulting mixture was refluxed for 1.5 hours over a water bath. At the conclusion of the refluxing the product precipitated as crystals. Upon distilling off the ethanol, needle crystals were obtained. Repeated recrystallization from 1.8 l of ethanol gave 7.4 g of intended compound having a melting point of 285° to 286° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[C:29]([N:31]=[C:32]=[O:33])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:27]=2[Cl:26])=[N:9]1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 4.48 (m, 2H), 6.09 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.32 (t, J=8.2 Hz, 2H), 7.40-7.45 (m, 2H), 10.66 (br s, 1H); MS (m/z): 455.21 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(Cc2ccc(OC)cc2)c2ccccc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 24.8 %

Procedure:
Methyl 3-indazolylcarboxylate (2.0 g, 11.4 mmol) was dissolved in DMF (20 ml). To the resulting solution were added 4-methoxybenzyl chloride (1.7 ml, 12.5 mmol) and potassium carbonate (2.35 g, 17.0 mmol). The resulting mixture was stirred at 80° C. for 15 hours. After cooling, the reaction mixture was poured in water (50 ml), followed by extraction with ethyl acetate (200 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, methyl 1-(4-methoxybenzyl)-3-indazolylcarboxylate (polar fractions, 838 mg, 25%) was obtained as a pale yellow oil and 2(4-methoxybenzyl) isomer (non-polar fractions, 500 mg, 15%) was obtained as a pale yellow oil.