Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(S([N:13]([C@H:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:53]=[CH:52][C:29]([C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]5[S:40][CH:41]=[CH:42][CH:43]=5)[CH:36]=[CH:35][C:34]=4[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:31])=[CH:28][CH:27]=3)[CH2:21]2)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=O)=O)=CC=1)([O-])=O.SCC(O)=O.[OH-].[Li+].CCOC(C)=O>CN(C=O)C.CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][C@H:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]5[S:40][CH:41]=[CH:42][CH:43]=5)[CH:36]=[CH:35][C:34]=4[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:31])=[CH:52][CH:53]=3)[CH2:21]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@H](N(c3cccnc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@H](Nc3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 247 (0.65 g, 0.86 mmol) in DMF (5 mL) was added mercaptoacetic acid (0.103 g, 1.12 mmol) followed by solid lithium hydroxide (0.108 g, 2.58 mmol). The reaction mixture was allowed to stir at room temperature for 18 h and then at 70° C. for 4 h. The reaction mixture was concentrated, diluted with AcOEt and extracted with H2O, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give a yellow oil which was purified by flash chromatography (eluents: 100% EtOAc then 2.5% MeOH/1% Et3N/96.5% EtOAc and finally, 5% MeOH/1% Et3N/94% EtOAc) to provide title compound 248 (0.333 g, 68% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]1=[O:26].CC1C=CC=CC=1>O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2n1CCN1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 70.4 parts of 1-(phenylmethyl)piperazine, 39.4 parts of 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one and 360 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The methylbenzene-phase is washed three times with water, dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is boiled in 2,2'-oxybispropane. The whole is cooled on an ice-bath. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, yielding 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one; mp. 136.5° C.
Reaction SMILES: [OH:1]C(O)=O.[CH3:5][C:6]1([CH2:14]C#N)[CH2:11][CH2:10][CH2:9][C:8](C)([CH3:12])[O:7]1>>[CH3:5][C:6]([OH:1])([CH2:11][CH2:10][CH2:9][C:8](=[O:7])[CH3:12])[CH3:14]
Reactant: O=C(O)O
Reactant: CC1(C)CCCC(C)(CC#N)O1
Product: CC(=O)CCCC(C)(C)O

Procedure:
Taking an overall evaluation of the second and third reaction (which simulate a plant operating with recycle but without recycling the hydroxyketone), a 2,6,6-trimethyl-2-cyanomethyltetrahydropyran yield of 52.9 mol % is obtained with respect to the 2-methyl-heptan-2-ol-6-one introduced into the reaction. As the hydroxyketone conversion during each test is about 80%, it is foreseeable that the overall pyran nitrile yield would rise to around 66 mol % if the unconverted hydroxyketone was also recycled.
Reaction SMILES: [P:1](Cl)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:28][C:25]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:30])[F:31])=[C:20]2[C:24]=1[C:23](=[O:29])[CH2:22][CH2:21]2)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(Cl)Oc1ccccc1OC
Reactant: O=C1CCc2c(C(F)(F)F)ccc(O)c21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOP(=O)(Oc1ccccc1OC)Oc1ccc(C(F)(F)F)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Allyl O-(2-methoxyphenyl) chlorophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-trifluoromethyl-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-allyl O-(2-methoxyphenyl) O-(4-trifluoromethylindan-1-on-7-yl) phosphate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H-].[Na+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:21]([N:20]([CH3:24])[CH3:19])=[S:22])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CN(C)C(=S)Cl
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OC(=S)N(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (620 mg, 2.81 mmol) (Example 6) in DMF (20 mL) was added NaH (124 mg, 3.10 mmol, 60% dispersion in mineral oil). Once the gaseous evolution had subsided (˜10 min), dimethylthiocarbamoyl chloride (382 mg, 3.10 mmol) was added. The solution was stirred at rt for 16 h, then at 60° C. for an additional 8 h. The reaction mixture was cooled to rt, a saturated solution of NH4Cl added, and the aqueous phase was extracted with ether. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (8:1 hexanes/EtOAc) to give the title compound as a yellowish oil (590 mg, 68%). 1H NMR (400 MHz, CDCl3) 7.16 (d, 1H), 6.90 (s, 1H), 6.84 (dd, 1H), 4.18 (q, 2H), 3.63-3.51 (m, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 2.98-2.84 (m, 2H), 2.78 (dd, 1H), 2.49-2.37 (m, 2H), 1.85-1.75 (m, 1H), 1.29 (t, 3H); LC-MS: RT=3.18 min, (M+H)+ 308.1.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])[NH:6][CH:7]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])[NH:6][CH:7]=1
Reactant: O=c1ccccn1-c1ccc(-c2nc(CO)c[nH]2)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=c1ccccn1-c1ccc(-c2nc(CCl)c[nH]2)c(F)c1

Procedure:
Alternatively as shown in Scheme 4, 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above, is treated with 4-hydroxymethylimidazole II-1 in the presence of 8-hydroxyquinoline, and K2CO3 in DMSO. The resulting mixture is degassed before being charged with CuI to give 4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1. The compound 4-1 is treated with thionyl chloride to give 4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole which is then treated with NaN3 to result in 4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2. The azide 4-2 is reduced with Ph3P to give 4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3. The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound 21.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=2)=[CH:4][C:3]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](O)=[O:42])=[CH:37][CH:36]=2)[S:29]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[CH3:17][N:15]([CH3:16])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH2:40][O:39][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH:30]3[S:29][C:28](=[O:27])[NH:32][C:31]3=[O:33])=[CH:45][CH:44]=2)=[C:3]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C)c1cccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1cccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c1
Yield: 97.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-dimethylaminophenoxy)phenyl]-N-methylcarbamate (1.00 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.57 g), diethyl cyanophosphonate (0.91 g), triethylamine (0.57 g) and anhydrous tetrahydrofuran (40 ml) and the reaction mixture was purified to give the desired product (1.69 g).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:5]([S:14][CH2:15][CH2:16][CH3:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>C(O)(=O)C>[Cl:3][C:4]1[C:5]([S:14]([CH2:15][CH2:16][CH3:17])=[O:1])=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CCCSc1ncc(C(F)(F)F)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: CCCS(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 27 °C
Reaction time: 14 h

Procedure:
At 15-20° C., 8.4 g (0.124 mol) of 50% strength hydrogen peroxide were added over a period of 15 min with stirring to a mixture of 31 g (0.1213 mol) of 3-chloro-2-n-propylthio-5-trifluoromethylpyridine in 150 ml of acetic acid, the temperature increasing to 27° C. over a period of 6 h. The reaction mixture was stirred at 25° C. for 14 h and then poured into ice-water and extracted 3 times with methylene chloride. The organic phase was washed with water and saturated sodium bicarbonate solution, dried and concentrated under reduced pressure, giving 32 g (97.2% of theory) of the title compound of mp. 51-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)-acetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) following General Procedure L using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[C:22](/[F:28])\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[CH3:11]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([F:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)/C(F)=C\c1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(F)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reaction time: 3 h

Procedure:
A solution of ethyl (E)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-fluoropropenoate (3.79 g) in ethanol (80 mL) was hydrogenated over 10% Palladium-charcoal (0.74 g) at room temperature and pressure for 3 hrs. The mixture was filtered, concentrated in vacuo and the residue chromatographed twice on silica gel, firstly with 10% ethyl acetate in dichloromethane and then with 25% ethyl acetate in hexane as eluents to afford a gum. Crystallisation from ethyl acetate-hexane afforded the title compound, mp 65°-7° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[N:7]1[CH3:17]
Reactant: CNN(C)C(=O)Nc1ccccc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(-c2ccccc2)c(=S)n1C

Procedure:
A solution of 4.26 g (0.037 mol) thiophosgene in about 10 ml chloroform was added dropwise to a solution of 6.7 g (0.037 mol) 1,2-dimethyl-4-phenylsemicarbazide and 7.47 g (0.074 mol) triethylamine in 200 ml chloroform. A slightly exothermic reaction ensued. One hour after the addition was completed, the reaction mixture was heated under reflux for about 16 hours, cooled and evaporated under reduced pressure to give an oil residue. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a red viscous oil. The oil was chromatographed on 200 g of silica gel using dichloromethane as eluant. The major product (4 g) from the chromatography was a semisolid, which on trituration with ether gave the desired product as a light tan solid, m.p. 118°-122° C. Infrared spectrum of the product showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23].C[OH:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:19])=[O:26])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CO
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Product: CC1=C(CC(=O)O)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
(Z)-5-fluoro-2-methyl-1-[[4-(methylthio)-phenyl]methylene]-1H-indene-3-acetic acid (5 g, 14.7 mmoles) is dissolved in methanol (40 ml). The solution is added with 5.4 g (14.26 mmoles) of 73% w/w ε-phthalimidoperhexanoic acid, keeping the temperature at about 20° C. After 18 h, the solution is concentrated to 15 ml and cooled to 5° C. The precipitate is filtered and dried. 4.6 g of (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)-phenyl]methylene]-1H-indene-3-acetic acid (sulindac) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13]C(NC)=O>O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: CNC(=O)NC
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: O
Product: CNC(=O)c1ccc(F)cc1N
Temperature: 150 °C

Procedure:
A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH2:27])[CH2:23][O:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][O:22]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC3COC(C)(C)O3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). 2.2-Dimethyl-1,3-dioxolane-4-methanamine (216 mg; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml). Title compound precipitates with addition diethyl ether, affording after filtration, Compound (14) as a white powder (65 mg; 46%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[CH:12][N:11]=[C:10]3[NH2:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)N.N[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[C:1]1([C:7]2[N:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:13]=[CH:12][N:11]=[C:10]3[NH:23][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncnc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reactant: CN1CCN(CCCN)CC1
Agent: NS(=O)(=O)O
Product: CN1CCN(CCCNc2ncnc3nc(-c4ccccc4)c(-c4ccccc4)nc23)CC1
Yield: 17 %

Procedure:
6,7-Diphenyl-pteridin-4-ylamine (200 mg, 0.669 mmol) and sulfamic acid (300 mg, 1.91 mmol) were dissolved in 4 ml 1-(3-aminopropyl)-4-methylpiperazine. The mixture was reflux for overnight. Preparative HPLC was used to isolated the product. 50 mg (6,7-Diphenyl-pteridin-4-yl)-(3-(4-methyl-piperazin-1-yl)-propyl)-amine was obtained. Yield: 17%, ESI-MS: [M+H]+, 441
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][CH:19]=[CH2:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[CH2:15])=[CH:6][CH:7]=1
Reactant: C=CCCC(C)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and hex-5-en-2-one.
Reaction SMILES: CN(C)S([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[C:8]([Br:15])[CH:7]=1)(=O)=O.BrC1C=C([F:24])C=C([N+]([O-])=O)C=1C>>[Br:15][C:8]1[CH:7]=[C:6]([F:24])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: CN(C)S(=O)(=O)c1cc(Br)c2cc[nH]c2c1
Product: Fc1cc(Br)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 4-bromo-1H-indole-6-sulfonic acid dimethylamide using 1-bromo-5-fluoro-2-methyl-3-nitro-benzene in place of 3-bromo-4-N,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (6.06 g, 33%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:28])[CH2:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29]I>>[C:1]1([CH:7]([O:14][C:15](=[O:28])[CH:16]([C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:26][CH3:27])[CH3:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)OC(c1ccccc1)c1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1C(C)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 46 %

Procedure:
Using the compound obtained in Example 342 as a starting material and also using methyl iodide (1 eq.) as a reagent, the same procedure of Example 1a gave the titled compound (yield, 46%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]5[CH2:21][CH2:22][CH:23]([C:25]([OH:27])=O)[CH2:24][C:19]=5[S:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.C(O)(=O)C(O)=O.[O:34]1[C:37]2([CH2:40][NH:39][CH2:38]2)[CH2:36][CH2:35]1>>[O:34]1[C:37]2([CH2:40][N:39]([C:25]([CH:23]3[CH2:22][CH2:21][C:20]4[C:13]5[C:12]([NH:11][C:9]6[CH:8]=[CH:7][C:5]7[NH:6][C:2](=[O:1])[S:3][C:4]=7[CH:10]=6)=[N:17][CH:16]=[N:15][C:14]=5[S:18][C:19]=4[CH2:24]3)=[O:27])[CH2:38]2)[CH2:36][CH2:35]1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: C1CC2(CNC2)O1
Agent: O=C(O)C(=O)O
Product: O=C(C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1)N1CC2(CCO2)C1

Procedure:
50 mg (125 μmol) (RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to example 2) were transformed in analogy to example 3 using 1-oxa-6-azaspiro[3.3]heptane ethanedioate (1:1) to give after working up and purification 31.7 mg (50%) of the title compound.
Reaction SMILES: [F:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:24]1([NH:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:30]([CH2:29][CH2:28][N:27]([CH:24]1[CH2:26][CH2:25]1)[CH:5]1[CH2:6][CH2:7][C:2]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])([F:1])[CH2:3][CH2:4]1)#[N:31]
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCC(=O)CC2)c([N+](=O)[O-])c1
Reactant: N#CCCNC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCN(C1CC1)C1CCC(F)(COc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 363B (200 mg) in dichloromethane (6 mL) was added 3-(cyclopropylamino)propanenitrile (64 mg) followed by sodium triacetoxyborohydride (184 mg). The mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (400 mL) and washed with 2N aqueous NaOH, water, and brine. After drying over Na2SO4, the mixture was filtered and evaporation of the solvent gave the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH2:13]([C:17]1[CH:22]=[C:21](O)[N:20]2[N:24]=[CH:25][CH:26]=[C:19]2[N:18]=1)[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([C:17]1[CH:22]=[C:21]([Cl:3])[N:20]2[N:24]=[CH:25][CH:26]=[C:19]2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1cc(O)n2nccc2n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCc1cc(Cl)n2nccc2n1

Procedure:
Phosphorus oxychloride (80 ml) and triethylamine (44 ml) were added to a toluene suspension (400 ml) containing 40 g of the crystals obtained in step (1). The reaction mixture was refluxed with heating for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The mixture was neutralized with sodium acetate and extracted with ethyl acetate. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:9) to provide 41 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine as a light yellow oily compound.