Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(CC(C)=O)C>[CH:6]1([NH:11][CH2:2][C:3]([NH2:5])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1CCCC1
Reactant: NC(=O)CCl
Solvent: CC(=O)CC(C)C
Product: NC(=O)CNC1CCCC1

Procedure:
To a solution of spiro[isobenzofuran-1(3 H),4'-piperidine] (14 g) in dichloromethane (160 ml) triethylamine (11 ml) was added. After cooling to 10° C. a solution of chloroacetylchloride (8 ml) in dichloromethane (10 ml) was added dropwise during 20 minutes. The reaction mixture was finally allowed to reach room temperature. The mixture was subsequently filtered through silica gel (eluted with ethyl acetate/n-heptane 60:40) affording 12 g of the α-chloroacetamide derivative. A mixture of the thus obtained α-chloroacetamide derivative (1.4 g) and cyclopentylamine in MIBK (25 ml) was refluxed for 2 h. The solvent was evaporated in vacuo and the cyclopentylamino derivative was extracted from an alkaline (pH>9) aqueous solution with ethyl acetate. The organic phase was worked up as above yielding 2.0 g of the α-(cyclopentylamino)acetamide derivative as a visceous oil. To a solution of the α-(cyclopentylamino)acetamide derivative (2 g) in MIBK 1'-chloracetyl-spiro[isobenzofuran-1(3 H),4'-piperidine] (1.4 g) and potassium carbonate (1 g) were added. The mixture was refluxed for 3 h. After cooling to room-temperature the mixture was filtered through silica gel (eluted with 4 % triethylamine in ethyl acetate. Evaporation of the solvents afforded 2.4 g of the diamide which was reduced with LiAlH4 as described in example 1. The title compound 3a crystallized from a mixture of ethanol and acetone (1:4). Yield 1.3 g, mp 258°-260° C. 1H NMR (DMSO-d6) δ1.50-2.45 (m,16 H), 3.25-3.80 (m,17 H), 5.05 (s,4 H), 7.10-7.40 (m, 8 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[O:18]([CH2:25]C(Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:29]([N:31]1[C:43]2[CH:42]=[CH:41][C:40]([NH2:44])=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30]>>[Cl:14][CH:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:25][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:9]([C:15]([NH:44][C:40]2[CH:41]=[CH:42][C:43]3[N:31]([CH2:29][CH3:30])[C:32]4[C:37]([C:38]=3[CH:39]=2)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:17])[CH2:10]1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CCl)CN3C(=O)COc3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=488.6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.81 g), triethylamine (1.4 cc) and 4-(4-chlorophenyl)piperidine (1.96 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization firstly from boiling acetonitrile (12 cc) and then from boiling acetonitrile (17 cc), 2-{3-[4-(4-chlorophenyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 111° C.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4])[NH2:2].Cl.[C:16](=[NH:21])(OCC)[CH3:17]>>[NH:21]=[C:16]([NH:2][NH:1][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:4])[CH3:17]
Reactant: CCOC(C)=N
Reactant: COC(=O)c1cccc(C(=O)NN)c1
Agent: Cl
Product: COC(=O)c1cccc(C(=O)NNC(C)=N)c1

Procedure:
Prepared analogously to the method described for intermediate product 1a) from methyl 3-hydrazinocarbonyl-benzoate and ethyl acetimidate hydrochloride. White solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[CH:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Lithium hydroxide hydrate (0.12 g; 2.82 mmole) dissolved in water (10 ml) was slowly added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxy-phenyl}ethoxy)phenyl]propanoic acid ethyl ester (1.12 g; 2.56 mmole) in tetrahydrofuran (30 ml). After stirring at room temperature for 3 hours, water (50 ml) was added and tetrahydrofuran was removed by evaporation in vacuo. The water residue was acidified with hydrochloric acid (2M) and extracted three times with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo to give 1 g (yield 96%) of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoic acid.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)[C:31]([F:42])=[CH:30][N:29]=1.[NH2:43][C:44]1[CH:52]=[C:51]2[C:47]([CH:48]=[CH:49][NH:50]2)=[CH:46][CH:45]=1>>[F:42][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[N:33][C:28]([NH:43][C:44]2[CH:52]=[C:51]3[C:47]([CH:48]=[CH:49][NH:50]3)=[CH:46][CH:45]=2)=[N:29][CH:30]=1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Oc1cccc(Nc2nc(Nc3ccc4cc[nH]c4c3)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 6-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 18.13 min.; purity: 96%; MS (m/e): 336 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH2:43][CH2:44][S:45]2(=[O:49])=[O:48])=[CH:40][CH:39]=1>O1CCCC1.CN(C)C=O>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:47]=[C:46]4[C:41]([CH2:42][CH2:43][CH2:44][S:45]4(=[O:49])=[O:48])=[CH:40][CH:39]=3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: O=S1(=O)CCCc2ccc(CCCCOCCCCCCBr)cc21
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3ccc4c(c3)S(=O)(=O)CCC4)ccc2O1
Temperature: 50 °C
Yield: 83.3 %

Procedure:
To a solution of (1R)-2-amino-1-(2,2-dimethyl4H-1,3-benzodioxin-6-yl)ethanol (128 mg) in dry tetrahydrofuran (6 ml) and dimethylformamide (2 ml) was added diisopropylethylamine (0.066 ml) and 7-{4[(6-bromohexyl)oxy]butyl}thiochromane 1,1-dioxide (120 mg). The reaction mixture was heated at 50° C. for 17 h. The mixture was then concentrated in vacuo and the residue was purified by chromatography on a Biotage cartridge (8 g) eluting with dichloromethane-ethanol-aqueous ammonia solution (100:8:1) to give the title compound (134 mg). LCMS RT=2.74 min
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:23]1C=CC=CC=1>>[S:7]([NH2:23])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(S(N)(=O)=O)cc1

Procedure:
reacting an iodolactone of the formula ##STR60## with thionyl chloride and treating with ammonia to yield a primary amide of the formula ##STR61## treating the primary amide with hydroxy (tosyloxy) iodobenzene to yield a p-toluenesulfonic acid salt of the formula ##STR62## tosylating the p-toluenesulfonic acid salt with toluenesulfonyl chloride in pyridine to yield a tosylamine of the formula ##STR63## treating the tosylamine with zinc in acetic acid to yield a norbornene carboxylic acid of the formula ##STR64## treating the norbornene carboxylk acid sequentially with ozone and with sodium borohydride and an acidic workup to yield a gamma-lactone of the formula ##STR65## performing ammonolysis of the gamma-lactone to afford a primary amide diol of the formula ##STR66## reducing and protecting the amine with BOC to produce a tert-butyl carbamate diol of the formula ##STR67## and sequentially treating the tert-butyl carbamate diol with toluenesulfonyl chloride, trifluoroacetic acid and diisopropylethylamine to produce a tosylamine azanoradamantane of the formula ##STR68##
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:23]C(C)([O-])C.[K+].[C:29](=[S:31])=S>O1CCCC1>[CH3:23][S:31][C:29]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[N:20]=1
Reactant: CC(C)(C)[O-]
Reactant: S=C=S
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: -6.199999809265137 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of 3.18 kg of 4,5-dihydro-7-[3-(trifluoromethyl)-phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide in 30 L of tetrahydrofuran is cooled to 2.8° C. under nitrogen and stirred while 1370 g of potassium tert-butoxide is added portionwise over 25 minutes while maintaining a temperature less than 4° C. The reaction mixture is stirred at -6.2° C. for 45 minutes. To the reaction mixture is added 850 g of carbon disulfide through a dropping funnel over a 10 minute period while maintaining the temperature below 2° C. The funnel is rinsed with 500 ml of tetrahydrofuran and the reaction mixture allowed to stir for 45 minutes. While maintaining the temperature from -8° C. to 3.2° C.. 1870 g of methyl iodide is added dropwise through a dropping funnel. The funnel is rinsed with 500 ml of tetrahydrofuran and the reaction mixture allowed to stir for 1 hour. An additional 3804 g of methyl iodide is added. The reaction mixture is stirred for 50 minutes while cooling to -23.1° C. An additional 2530 g of potassium tert-butoxide is added over 2 hours while maintaining a temperature of -23.1° C. to 10.0° C. After half of the potassium tert-butoxide is added another 300 ml of methyl iodide is added. The remaining potassium tert-butoxide is added and the reaction mixture stirred while warming to room temperature overnight. The reaction mixture is diluted with 3 kg of ice and 10 L of water then added to 80 L of water with stirring. The reaction flask is rinsed with 26 L of water which is added to the ice and water containing the original reaction mixture. Stirring is continued for 40 minutes and the solids collected by filtration. The filter cake is washed with 20 L of water and dried at 30 mm Hg, 35° C. to afford 3.4 kg (90%) of the desired product.
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:15]([C:22](O)=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.C(OC[C@@H](N)CC(C)C)C>C(OCC)(=O)C>[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C@H:15]([C:22]([NH2:33])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCOC[C@@H](N)CC(C)C
Solvent: CCOC(C)=O
Solvent: CCCC(=O)O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of Nα -Nim -bis-BOC-histidine ethyl acetate solvale (1.92 g, 5.0 mmol), 4-methylmorpholine (0.55 mL, 5.0 mmol) and isobutyl chloroformate (0.65 mL, 5.0 mmol) in ethyl acetate (50 mL) was stirred in an ice bath under N2 for 15 minutes. A solution of (S)-1-ethoxy-2-amino-4-methylpentane (0.73 g, 5.0 mmol) in ethyl acetate (2 mL) was then added and the reaction stirred at room temperature for 20 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was flash chromatographed over silica gel. Elution with a mixture of 2% methanol and 98% chloroform afforded pure BOC-protected histidineamide (0.90 g).
Reaction SMILES: FC(F)(F)C([O-])=O.C(OC([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=2)([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:17]1)=O)(C)(C)C.[ClH:46]>O1CCOCC1>[ClH:46].[Cl-:46].[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=2)([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:17]1
Reactant: COC(=O)c1ccc(CCC[N+]2(CCCc3ccc(OC)cc3)CCCC(NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC[N+]2(CCCc3ccc(OC)cc3)CCCC(N)C2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-1-[3-(4-methoxycarbonyl-phenyl)-propyl]-1-[3-(4-methoxy-phenyl)propyl]-piperidinium trifluoroacetate (525 mg, 0.82 mmol) is dissolved in dioxane (10 ml), a 4 M solution of HCl in dioxane (10 ml, 40 mmol) is added, stirred at room temperature for 2 h and concentrated in vacuo. LC (method 004_CC_ZQ7): tR=1.80 min; Mass spectrum (ESI+): m/z=425 [M]+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].O.[NH2:7]N.[C:9]([NH:14][CH:15]([CH3:23])[C:16](=O)[C:17](OCC)=[O:18])(=[O:13])[CH2:10][CH2:11][CH3:12]>C(O)C>[C:9]([NH:14][CH:15]([C:16]1[C:17](=[O:18])[NH:4][C:2]([CH3:3])=[N:5][N:7]=1)[CH3:23])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CC(=N)N
Reactant: NN
Reactant: CCCC(=O)NC(C)C(=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC(=O)NC(C)c1nnc(C)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of acetamidine hydrochloride (66.2 g) in absolute ethanol (600 ml) was slowly added a solution of hydrazine hydrate (35 g) in absolute ethanol (20 ml) over 20 minutes. After completion of the addition stirring was continued at room temperature for 10 minutes. A solution of ethyl 3-butyramido-2-oxo-butyrate (151 g) in absolute ethanol (100 ml) was then added and the mixture heated at 65°-70° with stirring for 20 hours. The precipitated ammonium chloride was removed by filtration and the filtrate concentrated in vacuo whereupon the triazinone separated. Ethyl acetate (ca. 300 ml) was added to aid the precipitation and the solid was collected. The filtrate was concentrated to give a second crop which was combined with the first and recrystallised from ethanol, 28.6 g. A further recrystallisation from ethanol afforded an analytical sample, m.p. 235°-237°.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1N=C(NC2C=CC=C(O)C=2)C(F)=C[N:29]=1.N1C=CC=C(CN)C=1>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][CH2:20][C:25]2[CH:28]=[N:29][CH:22]=[CH:23][CH:24]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: NCc1cccnc1
Product: Oc1cccc(Nc2nc(NCc3cccnc3)ncc2F)c1
Yield: 62 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDCl3): δ 4.40 (d, J=6.3 Hz, 2H), 5.60 (br, 1H), 6.62-6.70 (m, 3H), 7.05 (br, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (dd, J=5.1 and 7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H), 8.49 (d, J=4.5 Hz, 1H), 8.66 (s, 1H); 19F NMR (282 MHz, CDCl3): δ −169.52; LCMS: ret. time: 9.41 min.; purity: 99.25%; MS (m/e): 312.01 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:4]([NH:6][CH3:7])=[O:5])[CH3:2].[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34](Br)[CH:33]=1>>[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:33]=[C:34]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=2[CH2:8][N:3]([CH2:1][CH3:2])[C:4]([NH:6][CH3:7])=[O:5])[CH:35]=[C:36]([Cl:38])[CH:37]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NC

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 1-ethyl-3-methyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.N1C=C[CH:13]=NN=1.[C:16]1([NH:22][N:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:32]([O-:35])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:16]1([N:22]2[CH:13]=[C:25]([CH:32]=[O:35])[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1cnnnc1
Reactant: O=C([O-])[O-]
Reactant: CC(=NNc1ccccc1)c1ccccc1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,4,6-Trichloro[1,3,5]triazine (1.83 g, 10.0 mmol) is added to DMF (2 mL), and maintained at 25° C. After the formation of a white solid, the reaction is monitored (TLC) until complete disappearance of the triazine. 1-Phenyl-2-(1-phenylethylidene)-hydrazine (1.0 g, 5.0 mmol) in DMF (15 mL) is added. After the addition, the mixture is then stirred at room temperature and monitored for completion (TLC) after which a 15% solution of Na2CO3 (20 mL) is added. The organic phase is extracted twice with 15 mL of diethyl ether. The organic layer is then dried (Na2SO4) and the solvent is removed in vacuo to afford the desired product. Yields of approximately 1.12 g (90%) of this product can be expected when the reaction is conducted on this scale. Mp 145° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][NH:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:26](=[S:28])=[S:27].[C:29]1([CH2:34]Cl)[S:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O>[CH2:1]([N:8]1[C:20]2[CH2:19][N:18]([C:26]([S:28][CH2:34][C:29]3[S:33][CH:32]=[CH:31][CH:30]=3)=[S:27])[C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1Cc2c(n(Cc3ccccc3)c3ccccc23)CN1
Reactant: ClCc1cccs1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)[C@H]1Cc2c(n(Cc3ccccc3)c3ccccc23)CN1C(=S)SCc1cccs1

Procedure:
In the same manner as described in Example 51, (3R)-9-benzyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.225 g), 10N NaOH (0.8 ml), carbon disulfide (0.24 ml), dimethylsulfoxide (30 ml) and 2-thenyl chloride (0.66 g) are reacted and treated to give the title compound (0.635 g) as pale yellow powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:9]=3[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH2:22]>CN(C=O)C>[Br:3][C:4]1[C:12]2[N:11]([CH2:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH2:20])[C:10]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:9]=3[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1
Reactant: C=C(CBr)c1ccc(F)cc1
Reactant: Cc1cc(Br)c2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cn1c2c(c3cc(C)cc(Br)c31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (49.8 mg, 21.67 mmol) was charged in DMF (3 mL) and cooled to 0° C. 6-Bromo-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.83 mmol) was added and stirred at 0° C. for 5 min. 1-(3-Bromoprop-1-en-2-yl)-4-fluorobenzene (195.25 mg, 0.917 mmol) dissolved in DMF (1 mL) was added at 0° C. and stirred at RT for 2 h. Ice was added and the resultant solid obtained was filtered. The product was purified on silica using 0-7% MeOH:DCM as eluent. Yield: 85 mg.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C[O-].[Na+]>CN(C=O)C>[NH2:10][C:9]1[C:3]2=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=[C:2]2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: N#Cc1c(Cl)ccc[n+]1[O-]
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc[n+]([O-])c2c1N
Yield: 60 %

Procedure:
To a solution of 3-chloro-2-cyanopyridine (40g, 0.29 mol) in 500 mL acetic acid added hydrogen peroxide (30%, 52 g, 0.45 mol) dropwise. After stirring at 90° C. for 18 h, the reaction is cooled to 25° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H2O is added dropwise. The reaction is concentrated to remove the bulk of the acetic acid and the residue is partitioned between 1M NaOH and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc to provide 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The N-oxide from above (12.2 g, 79 mmol) was taken up in DMF (160 mL) at 0° C. Methyl thioglycolate (7.1 mL, 79 mmol) was added followed by sodium methoxide (8.5 g, 160 mmol) in portions. The RXN was stirred for 1 h. The RXN was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc. 10.6 g (60%) of 3-amino-2-carbomethoxythieno[3,2-b]pyridine-4-oxide was obtained. The pyridine-N-oxide (10.6 g, 47 mmol) is mixed with phosphorous oxychloride (100 mL). The RXN is heated to 80° C. for 30 min. The RXN is concentrated and partitioned between CH2Cl2 and NaHCO3 sln. The CH2Cl2 layer is dried (MgSO4), filtered, cone, and chromatographed (5:1 hex:EtOAc). 8.3g (73%) of the 5-chloro and 2.0 g (18%) of the 7-chloro product were obtained: 1H NMR (300 MHz, CDCl3 (5-chloro)) δ3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M+H)+. 1H NMR (300 MHz, CDCl3 (7-chloro)) δ3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCI/NH3) m/e 243 (M+H)+.