Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([Br:5])(C)C.[F:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C(=O)(O)[O-].[Na+]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([F:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[C:21]([F:24])=[CH:20][N:19]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cccc(F)c1-c1nc2c(F)cnc(Cl)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(F)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 50 °C
Yield: 94.7 %

Procedure:
Trimethylsilyl bromide (0.92 mL, 6.85 mmol) was added to a suspension of 3-fluoro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (0.70 g, 2.28 mmol) in propionitrile (20 mL) at room temperature, under argon. The reaction mixture was heated at 50° C. for 16 hours. The reaction mixture was adjusted to pH 7 by careful addition of a saturated aqueous solution of sodium bicarbonate. The resultant mixture was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resultant solid was triturated with diethyl ether and dried under vacuum to afford the title compound as an off-white solid (0.76 g, 95% yield). LCMS (Method D): RT=3.87 min, m/z: 352 [M+H+].
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:11]#[N:12])[S:7][C:8]=1[S:9][CH3:10])(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C(#N)C>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:11]#[N:12])[S:7][C:8]=1[S:9][CH3:10])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CSc1sc(C#N)c(C)c1C(C)=O
Solvent: CC#N
Product: CSc1sc(C#N)c(C)c1C(=O)C=CN(C)C

Procedure:
To a solution of 4-acetyl-3-methyl-5-methylsulfanyl-thiophene-2-carbonitrile (10 mmol) in acetonitrile (5 mL) was added DMF-DMA (2 mL) and the resulting mixture heated at reflux for 18 hours. The reaction was concentrated and the residue triturated with diethyl ether (20 mL). The suspension was filtered and washed with ether to afford the desired product as a yellow solid.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[CH3:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[C:25]1=[CH2:26].CC(C)=O>ClC=C(Cl)Cl>[CH3:34][N:27]1[C:25]2([O:13][C:4]3[CH:5]=[C:6]([N:14]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16][CH2:15]4)[C:7]4[C:12]([C:3]=3[N:1]=[CH:26]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:24]([CH3:35])([CH3:23])[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: c1ccc2c(c1)CCN2
Solvent: CC(C)=O
Solvent: ClC=C(Cl)Cl
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(cc(N3CCc4ccccc43)c3ccccc13)O2

Procedure:
A mixture of 1-nitroso-2-naphthol (17.3 g; 0.10 mol) and indoline (23.8 g; 0.20 mol) in trichloroethylene (150 ml) was heated under reflux for 10 min. A solution of 1,3-dihydro-1,3,3-trimethyl-2-methyleneindoline (17.3 g; 0.1 mol) in trichloroethylene (100 ml) was added in one batch and the resulting mixture heated under reflux for 1 h. The solution was evaporatedand the oily residue treated with acetone to yield 1,3-Dihydro-1,3,3-trimethyl-6'-(2,3-dihydroindol-1-yl)spiro [2H-indole-2,3'-3H-naphtho[2,1-b][1,4]oxazine] as a yellow solid (4.44 g; 10%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: ClCCCCBr
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Yield: 796.2 %

Procedure:
A solution of N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (3.29 g, 1.5 mmol) in dimethylformamide (33 ml) and potassium carbonate (4.14 g, 30 mmol) was reacted with 1-bromo 4-chorobutane (3.86 g, 2.5 mmol) at 60° C. for 2 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic phase was dried (magnesium sulphate), concentrated and the residue was purified by chromatography on silica gel. Elution with dichloromethane:ethyl acetate (8:2) then increased polarity to (6:4) yielded N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide as a white solid (3.7 g, 80% yield):
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7](/[CH:9]=[N:10]/[OH:11])=O)=[CH:3][CH:2]=1.O.[NH2:13][NH2:14]>CO>[N:13](=[C:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH:9]=[N:10][OH:11])[NH2:14]
Reactant: NN
Reactant: O=C(/C=N/O)c1ccccc1
Solvent: CO
Solvent: O
Product: NN=C(C=NO)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 2-isonitrosoacetophenone (50 g, 335 mmol) in methanol (500 ml) was treated with hydrazine monohydrate (19.5 ml, 402 mmol). The reaction mixture was stirred at room temperature for 20 h at which time the methanol was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 20% EtOAc in hexanes) to afford 37 g (227 mmol; 68%) of hydrazono-phenyl-acetaldehyde oxime as a white solid. δH (360 MHz; CDCl3) 7.22-7.42 (3H, m, aromatics), 7.42-7.60 (2H, m, aromatics), 7.99 (2H, br s, NH2), 8.26 (2H, br s, ArC(NNH2)CHNOH); m/z (ES+) 164 (M++H, 100%).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>CN(C=O)C.CC(N(C)C)=O>[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:31][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH2:21][C:20]3[CH:32]=[CH:33][CH:34]=[C:18]([F:17])[CH:19]=3)[N:23]=[CH:24]4)[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cnc(F)cc45)ccc32)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 80.1 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (30 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 5 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 1-(3-fluorobenzyl)-1H-indazol-5-amine (PCT Int. Appl., 2005058245, 30 Jun. 2005) (2.65 g, 11.0 mmol) in dry DMA (15 mL). The residue of 1-(3-fluorobenzyl)-1H-indazol-5-amine was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 65 h. It was poured into water (200 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (200 mL) was added and stirred at room temperature for 2 h. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The solid was collected by filtration and washed with water (5×25 mL). It was suspended in acetone (80 mL) and stirred at room temperature for 20 min. Water (160 mL) was added and stirred further for 1.5 h. The solid was filtered, dried and finally purified by a silica column (MeOH/dichloromethane: gradient from 0-10%) to give 6-fluoro-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]-pyrimidin-4-amine (202) (3.11 g, 80%) as a pale brown solid, mp 218-221° C.; 1H NMR δ [(CD3)2SO] 10.15 (s, 1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=1.3 Hz, 1H), 8.28 (br s, 14, 8.19 (poorly resolved d, J=0.7 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.15-7.01 (m, 3H), 5.71 (s, 2H). Anal, Calcd for C21H14F2N6: C, 64.94; H, 3.63; N, 21.64. Found C, 65.21; H, 3.71; N, 21.63.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NN1CCOCC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCOCC2)[nH]n1
Yield: 27 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (33 mg, 27%) which was obtained as a colorless oil. MS: m/e=364.4 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:15]([CH2:16]C)=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@@H:21]([CH3:23])[OH:22].O>CS(C)=O>[Cl:7][C:8]1[C:15]([CH3:16])=[C:14]([NH:19][C@H:20]([C@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
K2CO3 (3.15 g, 22.8 mmol) was added to a solution of 2-chloro-3-ethyl-4-fluorobenzonitrile (2.1 g, 11.4 mmol) and D-allo-threonine (2.04 g, 17.1 mmol) in DMSO (25 mL) at room temperature The reaction mixture was heated to 80° C. and stirred for 72 h then allowed to cool to room temperature. H2O (200 mL) was added and the brown solution was extracted with MTBE (200 mL). The aqueous layer was cooled to 0° C. and solid citric acid monohydrate was added in 200 mg portions until the evolution of gas ceased. The aqueous layer was then extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×300 mL), dried with Na2SO4, filtered and concentrated to provide the title compound (1.44 g, 32%): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.47 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 5.46 (d, J=8.7 Hz, 1H), 4.55-4.43 (m, 1H), 4.27 (dd, J=5.9 Hz, 8.7 Hz, 1H), 2.90-2.81 (m, 2H), 1.33 (d, J=6.3 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOC(C)=O>C(Cl)Cl.CCCCCC>[Br:20][CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: BrBr
Reactant: CCOC(=O)/C=C/CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)/C=C/CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Triphenyl phosphine (295 g, 1.12 mol) and methylene chloride (665 mL) were introduced into a 3 L one-neck flask and were stirred for 10 minutes at 0° C. And then, bromine (179.3 g) dissolved in methylene chloride (665 mL) was slowly added as droplets therein for 1 hours. At this time, the temperature of the reactor was maintained to be 0° C. The reaction product was further stirred for 30 minutes after all of bromine was added. (E)-ethyl 4-hydroxybut-2-enoate (133 g, 1.02 mol) dissolved in methylene chloride (665 mL) was slowly added as droplets into the reaction mixture for 1 hours. At this time, the temperature of the reactor was also maintained to be 0° C. After all of (E)-ethyl 4-hydroxybut-2-enoate was added, the mixture was further stirred for 30 minutes at 0° C. (the reaction was confirmed with TLC, EtOAc:hexane=1:4). After washing the organic layer of the reaction product with water (900 mL×2), the organic layer was dried with anhydrous MgSO4, and then a large quantity of Ph3P═O was extracted in company with the product by filtering and concentrating the same. The triphenyl phosphine oxide was eliminated by filtering the product, after adding n-hexane (1 L) therein and stirring the same for 30 minutes with a mechanical stirrer. (E)-ethyl 4-bromobut-2-enoate of 160 g was obtained with a yield of 81.2% by concentrating the filtered solution under a decompressed condition and distillating the concentrated solution under vacuum condition.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[Cl:20][C:21]1[C:22]([CH3:26])=[N:23][NH:24][CH:25]=1>>[Cl:20][C:21]1[C:22]([CH3:26])=[N:23][N:24]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)[CH:25]=1
Reactant: Cc1n[nH]cc1Cl
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Product: Cc1nn(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)cc1Cl

Procedure:
Was prepared according to Example 6 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and 4-chloro-3-methyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17][CH2:18][CH2:19]Cl.C#C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([CH:19]=[CH:18][Cl:17])=[O:5]
Reactant: ClCCCl
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Agent: C#C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=CCl)c1cc(F)c(Cl)cc1Cl

Procedure:
113.75 g (0.5 mole) of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise to a suspension of 73 g of anhydrous aluminum chloride and 200 ml of dry 1,2-dichloroethane at 0°-10° C., while cooling with ice and stirring. Acetylene is passed in at 40°-50° C. for 6.5 hours. The reaction mixture is poured onto ice, the organic phase is taken up in methylene chloride and the mixture is subsequently extracted with methylene chloride. After drying with sodium sulphate, the solvent is distilled off in vacuo. 121.7 g of 2-chlorovinyl 2,4-di-chloro-5-fluoro-phenyl ketone are obtained as a crude product of melting point 65°-70° C. Distillation under a fine vacuum gives 99.8 g (78.7%) of pure product of boiling point: 124°-128° C./0.1 mbar and melting point 71°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[C:6]1=[O:13])=[O:4].C(N(CC)CC)C.CN1C=CN=C1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 75.8 %

Procedure:
In 95 ml of toluene, 4.756 g of Compound 2-1 obtained in Production Example 1 was dissolved. To the solution thus obtained, 3.12 ml of triethylamine and 1.76 ml of N-methylimidazole were added, and 3.38 g of 4-toluenesulfonyl chloride was added. The resulting mixture was stirred at room temperature for 100 minutes. After the reaction, water was added to the reaction solution thus obtained, and the organic layer was separated from the suspension. Thereafter, the aqueous layer was extracted with toluene and then blended with the organic layer previously obtained. The resultant organic layer thus obtained was washed with an aqueous solution of 1 mol/l hydrochloric acid and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 5.397 g of Compound 3-1-2.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:22][CH2:23][CH3:24])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1>>[C:1]1([C:7]#[C:8][CH2:9][O:18][C:17]2[CH:19]=[CH:20][C:12]([C:11]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:14]=2[O:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: BrCC#Cc1ccccc1
Product: CCOC(=O)c1ccc(OCC#Cc2ccccc2)c(OC)c1
Yield: 70 %

Procedure:
3-Phenylprop-2-ynyl bromide was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 4-(3-phenylprop-2-ynyloxy)-3-methoxybenzoate in 70% yield, m.p. 62°-65° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 61% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:29]1[C:34]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)=[CH:33][CH:32]=[CH:31][N:30]=1>C1COCC1>[CH3:60][O:59][C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:42]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)[C:37]2[N:36]=[C:35]([C:34]3[C:29]([NH:15][C:13]4[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=5)[CH:14]=4)=[N:30][CH:31]=[CH:32][CH:33]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:58][CH:57]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ccc(COc2cc(N)ccn2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Nc3ncccc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 2-(4-methoxybenzyloxy)pyridin-4-amine (0.500 g, 2.171 mmol) in THF (10 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (6.51 mL, 6.51 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. 4-(2-Fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.161 g, 2.61 mmol) was added to this reaction mixture. After the addition, the resulting mixture was stirred at 0° C. for 10 min and then removed from the ice bath and stirred for 2 h at rt. The reaction was quenched with water. The resulting mixture was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 20% to 30% EtOAc in hexanes) to give the product as a white solid (0.950 g). m/z (ESI, +ve ion) 656.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.36 (s, 1H); 8.85 (d, J=7.75 Hz, 1H); 8.40 (d, J=4.38 Hz, 1H); 7.98 (d, J=5.41 Hz, 1H); 7.50 (s, 1H); 7.43 (d, J=8.33 Hz, 2H); 7.21 (d, J=8.18 Hz, 4H); 7.02 (d, J=4.38 Hz, 1H); 6.73-6.98 (m, 7H); 5.32 (s, 2H); 4.85 (br. s., 4H); 3.69-3.96 (m, 9H); 2.62 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc(C)cc2)CC1

Procedure:
4-(methyl)phenyl chloroformate (5.00 g, 29.3 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (5.03 g, 22.6 mmol) according to general procedure 1. Yield=5.20 g, 90%. m/z MH+=258.11. HPLC rt=13.0 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[N:18]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[N:17]=[C:16]([CH2:24][CH3:25])[C:14]=2[N:15]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[C:13]2[N:18]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[N:17]=[C:16]([CH2:24][CH3:25])[C:14]=2[N:15]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCOCCn1nc(CC)c2nc(Cl)nc(Cl)c21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOCCn1nc(CC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of 2-amino-4-picoline (4.32 g, 40 mmol) and 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidine from step 4 (5.78 g, 20 mmol) was treated with THF (25 mL) and cooled to 0° C. The mixture was stirred and treated with 1 M LiN(TMS)2 in THF (40 mL, 40 mmol) at a rate such that the temperature was kept below 5° C. The mixture was stirred for 30 min and was then treated with 10% citric acid solution until pH 6-7 was achieved. The mixture was partially concentrated under reduced pressure. The mixture was then stirred at 5° C. for 1 h. The resulting solid was collected by suction filtration and washed with water (40 mL). The solid was dried in a vacuum oven at a temperature less than 60° C. to afford 7.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[CH:11]=[CH2:12]>>[CH2:9]([C:10]([CH:11]1[CH2:12][CH2:5][C:4]([CH3:6])=[C:2]([CH3:1])[CH2:3]1)=[O:13])[CH:8]([CH3:14])[CH3:7]
Reactant: C=CC(=O)CC(C)C
Reactant: C=C(C)C(=C)C
Product: CC1=C(C)CC(C(=O)CC(C)C)CC1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
45.3 g of 2,3-dimethylbutadiene are added to 47.5 g of 5-methyl-hex-1-en-3-one at initially 100° C., at a rate such that the temperature does not drop below 90° C. The mixture is then kept for 1 hour at 100° C. and 30 minutes at 115° C., the excess dimethylbutadiene is distilled off, and the residue is distilled under reduced pressure. 64 g of 3,4-dimethylcyclohex-3-en-1-yl isobutyl ketone, of boiling point 99°-101° C./3 mm Hg, are obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:3]=1.[NH4+].[Cl-]>CO.O1CCOCC1.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]([C:8]#[N:9])[CH:5]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(Br)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Yield: 76.9 %

Procedure:
0.184 g (0.0005 mol) of 6-bromo-4-(4-nitrobenzenesulphonyl)-pyridine-2-carbonitrile was dissolved in 10 ml of methanol/dioxane, treated with 0.37 g of iron powder and a solution of 0.37 g of NH4Cl in 10 ml of water and boiled at reflux for 2 hrs. Then, the reaction mixture was filtered and the filter cake was rinsed with methanol and ethyl acetate. The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with sat. NaHCO3 solution, water and sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.13 g (75%) of 4-(4-aminobenzenesulphonyl)-6-bromopyridine-2-carbonitrile as yellow crystals; m.p.: 186-188° C.