Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:14].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N+:4]2[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cn1ccnc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: Cn1cc[n+](Cc2ccc(C(F)(F)F)cc2)c1
Product: [Br-]
Yield: 107.4 %

Procedure:
By carrying out the procedure as in Step 1 of Example 10, but starting with 2 g of N-methylimidazole and 8.73 g of 4-trifluoromethylbenzyl bromide, at the reflux temperature of toluene for 2 hours, 8.4 g of 1-(4-trifluoromethylbenzyl)-3-methylimidazolium bromide are obtained in the form of an orange-yellow solid whose characteristics are the following:
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.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(Br)c1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1ccccc1)n1cnc2c(Cl)nc(Cl)nc21
Product: CC(c1ccccc1)n1cnc2nc(Cl)nc(Cl)c21

Procedure:
Using the same general procedure of Preparation A, 4.12 g of 2,6-dichloropurine, 3.32 g of potassium carbonate and 4.44 g of 1-bromoethylbenzene gave 830 mg of 2,6-dichloro-7-(1-phenylethyl)purine and 1.3 g of 2,6-dichloro-9-(1-phenylethyl)purine.
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[O:7]C(=S)OC1C=CC=CN=1.[Na].[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][CH2:26][CH:25]([N:29]([CH3:31])[CH3:30])[CH2:24]2.C(N(CCC)C1CC2C(=C(N)C=CC=2)NC1)CC>>[CH3:30][N:29]([CH3:31])[CH:25]1[CH2:26][N:27]2[C:2](=[O:7])[CH2:3][O:18][C:19]3[C:28]2=[C:23]([CH:22]=[CH:21][CH:20]=3)[CH2:24]1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CN(C)C1CNc2c(O)cccc2C1
Agent: CCCN(CCC)C1CNc2c(N)cccc2C1
Agent: [Na]
Product: CN(C)C1Cc2cccc3c2N(C1)C(=O)CO3

Procedure:
This compound was prepared by following the procedure of Example 56 part B, but substituting ethyl bromoacetate for di (2-pyridyl)thiocarbonate and the sodium salt of 1,2,3,4-tetrahydro-8-hydroxy-N, N-dimethyl-3-quinolinamine for 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine.
Reaction SMILES: [Na+].[Na+].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([CH3:39])[CH:10]=[CH:11][C:12]=1[S:13]([NH:16][C:17]1[C:26]2[C:25]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:24][C:23]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:22][C:21]=2[C:20]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:19][CH:18]=1)(=[O:15])=[O:14])([O-])=O.[H][H]>[Pd].O>[NH2:4][C:7]1[CH:8]=[C:9]([CH3:39])[CH:10]=[CH:11][C:12]=1[S:13]([NH:16][C:17]1[C:26]2[C:25]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:24][C:23]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:22][C:21]=2[C:20]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:19][CH:18]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(N)c1
Reaction time: 16 h
Yield: 67.5 %

Procedure:
A mixture of 8.0 g of 8-(3-nitro-p-toluenesulfonamido)-1,3,5-naphthalene trisulfonic acid trisodium salt, 160 ml of water and 800 mg of 10% palladium on carbon catalyst is hydrogenated on a Parr shaker until no additional hydrogen is absorbed. The resulting mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is dissolved in hot water and filtered. The filtrate is triturated with ethanol until cloudiness persists, then is allowed to stand at room temperature for 16 hours. The mixture is filtered and the filtrate evaporated to afford a gummy material which is dissolved in a small amount of water and triturated with ethanol. An additional 200 ml of ethanol is added and the mixture is stirred for one hour to provide a solid. The solid is collected and washed with ethanol and ether to yield 4.6 g of 8-(3-amino-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt as a light tan powder.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Cl-].[NH4+:12].[C-:13]#[N:14].[Na+].[Cl-].[Na+]>N>[NH2:12][C:6]1([C:13]#[N:14])[CH2:7][CH2:8][N:3]([N:2]([CH3:10])[CH3:1])[CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CN(C)N1CCC(=O)CC1
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [Na+]
Product: CN(C)N1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.3 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) is dissolved in 135 ml aqueous ammonia (25%). To this solution 3.55 g ammonium chloride is added, then 4.34 g sodium cyanide. The reaction mixture is stirred at room temperature for 18 hours. Then the mixture is saturated with sodium chloride, and four times extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is evaporated, to yield 5.6 g 4-Amino-1-dimethylamino-piperidine-4-carbonitrile as a yellow oil. 1H-NMR (CDCl3): 2.95 ppm (m, 2H), 2.65 ppm (m, 2H), 2.40 ppm (s, 6H), 2.05 ppm (m, 2H), 1.80 ppm (m, 2H), 1.75 ppm (s, broad, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:13])=[O:10])[S:5][C:6]=1[Br:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)c(Br)s1
Product: O=C(Cl)c1cc(Br)c(Br)s1

Procedure:
Using the procedure of Example 32, 2.86 g (10.0 mmoles) of commercially available 4,5-dibromo-2-thiophenecarboxylic acid was added to 10 ml of thionyl chloride to give a heterogeneous mixture. Heating the reaction mixture helped the solution become homogenous. Concentration of the reaction solution gave 3.15 g of crude 4,5-dibromo-2-thiophenecarbonyl chloride as a brown oil. The crude acid chloride, dissolved in 10 ml of N,N-dimethylformamide was slowly added to 1.76 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine in 40 ml of N,N-dimethylformamide under the conditions of Example 32. Workup gave 2.82 g of orange solid which was recrystallized from 2-butanone to give 1.61 g (3.37 mmoles, 40% yield) of pure title compound as a yellow solid, m.p. 229°-31° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH:9]([O:19][CH2:20][CH3:21])[C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([O:8][CH2:6][CH3:7])[O:19][CH2:20][CH3:21])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CCOC(OCC)c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(OCC)c1cccc(CCOS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 g) in dichloromethane (0.2 mL) was added to a stirred solution of 2-(3-(diethoxymethyl)phenyl)ethanol (example 20, step c) (0.23 g) and triethylamine (0.429 mL) in dichloromethane (2.5 mL) cooled in an ice bath. After 1 h, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.28 g.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[S:2]1.[OH:17]O>CC(C)=O>[O:17]=[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[S:2]1
Reactant: CS(=O)(=O)NC(=O)CCCCC1CCSS1
Reactant: OO
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=O)CCCCC1CCS(=O)S1
Reaction time: 8 h

Procedure:
500 mg of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (prepared as described in Example 2) were dissolved in 10 ml of acetone, and 0.44 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the solution, whilst ice-cooling. The mixture was stirred and then left to stand at room temperature overnight. At the end of this time, a further 0.2 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the reaction mixture, and then the mixture was stirred at room temperature for 30 minutes, and then stirred on an oil bath at 50° C. for 1 hour. The mixture was then left to stand at room temperature for 3 days, after which it was stirred on an oil bath at 50° C. for 10 hours; it was then left to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by reverse phase preparative silica gel column chromatography, using 1:3 and 2:3 by volume mixtures of acetonitrile and water as the eluent. The solvent was evaporated from the eluted fraction thus obtained under reduced pressure, and the fraction was lyophilised, to obtain 0.15 g of the title compound (diastereomer mixture) as a colorless oil having an Rf value of 0.43 (silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=O)[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[S:31])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1C
Solvent: Cc1ccccc1
Product: CCc1cc(CCc2nc3ccccc3o2)c(=S)[nH]c1C
Yield: 24.7 %

Procedure:
A mixture of 3-[2-(benzoxazol-2-yl)-ethyl]-5-ethyl-6-methyl pyridin-2(1H)-one (150 mg, 0.53 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) (485 mg, 1.2 mmol) in dry toluene (4 mL) was refluxed for 6-10 hours. The solvent was evaporated and the reaction residue was flash chromatographed on silica gel eluting with 0.5% methanol/chloroform. The appropriate fractions were combined and crystallized from ethyl acetate to yield 80 mg of slightly impure product. This material was re-chromatographed on silica gel eluting with chloroform. The appropriate fractions were combined, the solvent evaporated, and the residue recrystallized from boiling diethyl ether, after addition of sufficient methylene chloride to effect complete dissolution, to yield 39 mg (24%) of pure product, m.p. 199°-201° C.
Reaction SMILES: [C:1]([C:3]([NH:8]C(=O)OCC1C=CC=CC=1)([CH2:5][CH2:6][F:7])[CH3:4])#[N:2].[Cl:19]CCl.C1CCCCC1>[Pd]>[ClH:19].[ClH:19].[F:7][CH2:6][CH2:5][C:3]([CH3:4])([NH2:8])[CH2:1][NH2:2]
Reactant: ClCCl
Reactant: CC(C#N)(CCF)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Product: CC(N)(CN)CCF
Product: Cl
Reaction time: 3 h

Procedure:
1.00 g (4.00 mmol) of rac-benzyl (2-cyano-4-fluorobutan-2-yl)carbamate from Example 73A were dissolved in 114 ml ethanol/glacial acetic acid (1/1), and 0.85 g of palladium on activated carbon (10%) were added. The reaction mixture was hydrogenated in an autoclave at 30-50 bar for 3 h. The reaction mixture was filtered through a fluted filter, rinsed with ethanol and then filtered once again through a Millipore filter. The filtrate was admixed with 10 ml of hydrogen chloride solution (2 N in diethyl ether) and then concentrated by evaporation. This gave 1.04 g of the target compound which was used in the subsequent stage without further purification.
Reaction SMILES: [ClH:1].Cl.N[C@@H](CC)[C@H](O)C(NC1CC1)=[O:7].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[CH2:17][OH:18].[N+:22]([CH:24]([CH2:26][CH2:27][CH3:28])[CH3:25])#[C-:23]>>[ClH:1].[ClH:1].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[C@H:17]([OH:18])[C:23]([NH:22][CH:24]([CH2:26][CH2:27][CH3:28])[CH3:25])=[O:7]
Reactant: [C-]#[N+]C(C)CCC
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)CO
Agent: Cl
Product: CCCC(C)NC(=O)[C@@H](O)[C@@H](N)CCC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-aminopentan-1-ol in the first step (A1), and using 2-isocyanopentane in the third step (A3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:13]([CH2:26][OH:27])[CH2:12][N:11]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1.[CH2:39]([CH:41]1[O:43][CH2:42]1)Br.[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]=[C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:13]([CH2:26][O:27][CH2:39][CH:41]([OH:43])[CH2:42][NH:48][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:12][N:11]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: CC(C)(C)N
Reactant: BrCC1CO1
Reactant: COc1ccc(CN2CC(CO)N(Cc3ccc(OC)c(OC)c3)C2=Nc2c(Cl)cccc2Cl)cc1OC
Solvent: CO
Product: COc1ccc(CN2CC(COCC(O)CNC(C)(C)C)N(Cc3ccc(OC)c(OC)c3)C2=Nc2c(Cl)cccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
0.13 g of Na were dissolved in 20 ml of methanol. After dissolution, 2.8 g of (9) (0.5 mol) in 10 ml of methanol were added. The mixture was refluxed for one hour. Then the solvent was evaporated. The residue was dissolved in 40 ml of DMF and 0.48 ml (5.6 mmol) of epibromohydrin were added. The mixture was stirred for 18 hours at room temperature, after which time the DMF was evaporated. The crude mixture was dissolved in 30 ml of ethanol and 1.1 g (15 mmol) of tert-butylamine were added. After evaporation of the solvent and EtOAc/water extraction, the organic layer was dried over MgSO4 and filtered. Concentration gave 3.2 g of crude product which was separated over a silica gel column using EtOAc/MeOH/ET3N: (8:1:1) as solvent. After purification, 2.1 g of (10) were obtained (yield 61%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:4][C:3](=[O:5])[CH2:2]1.[C:7]1(=[O:14])[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH2:8]1>>[CH3:7][O:5][C:3]1[CH2:4][C:1](=[O:6])[CH:2]=1.[CH3:1][O:13][C:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:14])[CH:8]=1
Reactant: O=C1CC(=O)C1
Reactant: O=C1CCCC(=O)C1
Product: COC1=CC(=O)C1
Product: COC1=CC(=O)CCC1
Reaction time: 24 h

Procedure:
Using the procedure of Example 2 with stirring of the reaction mixture for up to one day, 3-methoxycyclobut-2-en-1-one and 3-methoxycyclohex-2-en-1-one are prepared from 1,3-cyclobutanedione and 1,3-cyclohexanedione.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([F:7])[CH:4]=[C:3]1[C:8]([O:10]C)=O.C(O/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C1(C)C(S(O)(=O)=O)=CC=CC=1.CC(C)([O-])C.[Na+]>C(O)C.O>[F:7][C:5]1[CH:4]=[C:3]2[C:8]([OH:10])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[N:1][N:2]2[CH:6]=1
Reactant: COC(=O)c1cc(F)cn1N
Reactant: CCO/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn2cc(F)cc2c1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate (0.980 g, 6.20 mmol), (E)-ethyl 3-ethoxyacrylate (1.25 g, 8.68 mmol) and toluenesulfonic acid (0.059 g, 0.310 mmol) in ethanol (15 mL) was heated at 85° C. for 2 h then at reflux (100° C. bath) for an additional 2 h. The mixture was cooled and concentrated to remove the ethanol/water and additional ethanol was added and reconcentrated. The process was repeated until all of the water had been removed then residue was dissolved in ethanol (15 mL) and sodium tert-butoxide (1.190 g, 12.39 mmol) was added to make orange clear solution. This mixture was heated at 85° C. for 1 h, then cooled and concentrated to remove the ethanol and the reaction mixture was neutralized with HCl in dioxane (0.5 mL of 4N solution) then concentrated to afford a tan semi solid. This material was slurried in water and stirred for 1 h and the resulting solid was collected and rinsed with water and filtered and dried to afford the title compound (740 mg, 3.30 mmol, 53.3% yield) as a light yellow solid. HPLC (condition B): retention time=3.57 min. LCMS (condition B): m/z 224.9+ve.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[Cl:17]N1C(=O)CCC1=O.CN(C)C=O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Cl:17])=[C:4]([Cl:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)c(Cl)c(NCC2(CO)CCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.24 g, 2.0 mmol) were added N-chlorosuccinimide (0.27 g, 2.0 mmol) and dimethylformamide (1.5 ml), and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give colorless prism crystals (0.3 g, 54.2%), m.p. 179-181° C. (acetone).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9]3[CH:12]=[N:13][N:14]([CH3:15])[C:8]=3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)CCC.[Cl-].[Li+]>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>[CH3:15][N:14]1[C:8]2[C:7](=[O:16])[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:11]=3[NH:10][C:9]=2[CH:12]=[N:13]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Cn1ncc2[nH]c3c(Br)cccc3c(=O)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cn1ncc2[nH]c3c(-c4ccccc4)cccc3c(=O)c21
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A mixture of 5-bromo-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 5, 50 mg, 0.18 mmol), tributylphenyltin (0.12 ml, 0.36 mmol), tetrakis(triphenylphosphine)palladium (0) (62 mg, 0.054 mmol) and lithium chloride (19 mg, 0.45 mmol) in 1,4-dioxane (2 ml) was refluxed for 16 h. After cooling to room temperature, the mixture was evaporated, dissolved in ethyl acetate (20 ml) and the insoluble material was filtered off. The filtrate was concentrated in vacuo and purified by preparative thin layer chromatography developing with ethyl acetate/hexane (1/2). The obtained solid was recrystallized from diethyl ether to afford 17 mg (33%) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[Cl:19])[C:14](Cl)=[O:15]>O1CCOCC1.O>[CH3:12][N:13]([S:17][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[Cl:19])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CCOC(=O)C(Cl)(SN(C)C(=O)Cl)C(=O)OCC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(Cl)(SN(C)C(=O)ON=C1SC(C)(C)C(=O)N1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.91g (0.011m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 5.0g (0.011m) of a 70 percent solution of N-methyl-N-(bis-ethoxycarbonylchloromethanesulfenyl) carbamoyl chloride and 1.11g (0.011m) of triethylamine in 100 ml of dioxane was stirred overnight at room temperature. The reaction mixture was diluted with water, the product was extracted into ethylacetate and the organic phase was washed with water, and dried over magnesium sulfate. Removal of the solvent gave a residual oil which was purified by chromatography through silica gel.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]([Cl:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[CH3:17][N:18]([CH3:21])[CH:19]=[O:20]>>[Cl-:14].[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]([C:19](=[O:20])[N:18]([CH3:21])[CH3:17])[CH:10]=[N+:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C(Cl)=Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Product: CN(C)C(=O)N(C=[N+](C)C)c1cccc(C(F)(F)F)c1
Product: [Cl-]

Procedure:
A mixture of 25.05 g (0.1 mol) of N-(3-trifluormethyl-phenyl-N,N-dimethyl-1-chloroformamidine and 20 g (0.3 mol) of dimethylformamide is stirred in the same way as described in Example 6.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC>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.O1CCOCC1>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1nccs1
Temperature: 130 °C
Yield: 36.1 %

Procedure:
A mixture of 4-bromo-5-nitrothiophene-3-carbonitrile (0.5 g, 2.1 mmol), 2-(tributylstannyl)thiazole (1.2 g, 3.2 mmol), dioxane (3.5 mL), and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.21 mmol) was heated by microwave to 130° C. for 30 min under nitrogen. The reaction mix was concentrated under reduced pressure, and the resulting dark oil was purified by column chromatography using a mobile phase of 20% EtOAc/hexanes to give 5-nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile (180 mg) as an oil. LCMS of this material revealed an m/z of 238.0 with a retention time of 1.807 min method [1].
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH2:1]([N:8]([CH3:38])[N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)n1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21
Reaction time: 0.25 h
Yield: 4 %

Procedure:
To a solution of tert-butyl 4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (prepared in example 25: 125 mg, 0.26 mmol) in 3.0 mL of DMF at 0° C. was added NaH (60% in oil, 31 mg, 0.78 mmol) in one portion. After 15 min, the mixture was treated with methyl iodide. HPLC check shows disappearance of starting material. Solvent was removed and the residue dissolved in ethyl acetate, washed with aqueous NaHCO3. The organic solution was dried, evaporated and then the residue was treated with methanol (0.5 mL) and HCl (4.0M in dioxane, 2.0 mL) at room temperature for 30 min. The solvent was removed and the residue was purified by preparative HPLC to give product as a white solid (4.1 mg, yield 4%).