Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Cl[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 150 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 2 ml of isopropanol, 32.3 mg (0.233 mmol) of 6-chloronicotinonitrile and 30.09 mg (0.233 mmol) of DIPEA are added, and the mixture is heated in a microwave at 150° C. for 1 h. Purification by preparative HPLC results in 47 mg (71% of theory) of the product.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[OH:13][N:12]=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([I:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C#N)ccc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(N)=NO)ccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a mixture of 4-iodo-3-methylbenzonitrile (3.59 g, 14.8 mmol) and hydroxylamine hydrochloride (2.05 g, 29.5 mmol) in methanol (75 mL) under nitrogen was added sodium bicarbonate (4.96 g, 59.1 mmol). The reaction mixture was stirred at room temperature for 5 min. and then immersed in an oil bath and heated at reflux for 2 h. The heterogeneous mixture was filtered, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure. The white solid residue was diluted with ethyl acetate (300 mL) but remained heterogeneous. The mixture was sonicated for 5 min and filtered under reduced pressure. By HPLC, the solid appeared to be inorganic. The filtrated was washed with (50 mL), and washed with a 10% aqueous solution of lithium chloride (50 mL), and washed with brine (50 mL). The combined aqueous layers were extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded N′-hydroxy-4-iodo-3-methylbenzimidamide (3.87 g, 14.0 mmol, 95% yield) as a white solid. The compound had an HPLC ret. time=0.993 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=276.8. 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3H), 4.85 (br. s., 2H), 7.13 (dd, J=8.32, 2.22 Hz, 1H), 7.51 (d, J=1.66 Hz, 1H), and 7.84 (d, J=8.32 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-:40].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:40])=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: O=C([O-])O
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 85.8 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>C(Cl)Cl>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:18]=[S:19])=[CH:16][C:6]=1[CH2:7][N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:14])[CH3:15])[CH2:9]1
Reactant: CN(C)C1CCN(Cc2cc(N)ccc2Cl)C1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(C)C1CCN(Cc2cc(N=C=S)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[1-(5-Amino-2-chloro-benzyl)-pyrrolidin-3-yl]-dimethyl-amine (Step f, 1.2 g, 4.7 mmol, 1.0 eq.) was dissolved into CH2Cl2 (100 ml) and 1,1′-thiocarbonyldiimidazole (0.85 g, 4.7 mmol, 1.0 eq.) was added. The reaction was stirred at RT for 2 h. TLC showed conversion of starting material into product. Concentrated down to dryness and purified by column chromatography (100% EtOAc) to give [1-(2-chloro-5-isothiocyanato-benzyl)-pyrrolidin-3-yl]-dimethyl-amine.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>C1COCC1.O>[Br:20][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[C:7](=[N:8][C:3]([NH2:2])=[N:4][CH:5]=3)[N:9]([CH3:21])[N:10]=2)[CH:17]=[C:16]([F:18])[C:15]=1[O:19][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2cc(F)c(OCCN3CCCC3)c(Br)c2)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in anhydrous THF (10 ml), K2CO3 (12 mg, 0.09 mmol) is added and the reaction mixture is stirred at room temperature for 10 minutes. Triphenylphosphine (116 mg, 0.44 mmol), DIAD (0.076 ml, 0.40 mmol) and 1-(2-hydroxyethyl)pyrrolidine (0.048 ml, 0.40 mmol) are added and the reaction mixture is heated to reflux for 20 hours. After cooling to room temperature the reaction mixture is diluted with water (˜15 ml) and extracted with EtOAc (3×50 ml). The combined organic portions are dried over MgSO4, filtered and concentrated in vacuo Purification of the crude residue by flash chromatography on silica firstly eluting the non-polar impurities with iso-hexanes:EtOAc (4:1 to 1:4) then eluting the product with EtOAc:MeOH:Et3N (4:1:0.01) affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=[O:9].[Cl-].[NH4+]>O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: ONc1ccccc1Cl
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
A suspension of 2-chloronitrobenzene (50 g, 0.318 mol) and ammonium chloride (16.9 g, 0.318 mmol) in 636 mL of water was warmed to 65° C. To the mixture was added in portions zinc (60 g, 0.955 mol) over 20 min, and the temperature was kept at 70° C.˜75° C. After stirring for 10 min, TLC showed the reaction was completed. The mixture was filtered and washed with water (˜70° C.). To the filtrate was added NaCl, then cooled to −10° C. After 1 h, the mixture was filtered and washed with pertrolume, and then dried to afford the desired hydroxylamine as a white solid (35 g, 76.9%), which was used to next step without purification. 1HNMR (400 MHz, DMSO): δ 8.36 (s, 2H), 7.16 (m, 2H), 6.79 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:32][CH:33]4[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]4)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC4CCC(O)CC4)nc3N(C3CCCC3)C2=O)c1F
Temperature: 10 °C
Yield: 87.9 %

Procedure:
To a solution of 0.511 g (1.13 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was added 0.39 g (3.39 mmol) of trans-4-aminocyclohexanol. The resulting mixture was heated at 1 10° C. oil bath temperature for 2 days under N2 atmosphere. The dioxane was evaporated. The crude product was purified by medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (88%) of title compound: mp 208° C.–212° C. (dec). MS (APCI) (m+1)/z 504.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2Cl)([O-:18])=[O:17].O>O1CCCC1>[N+:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccc([N+](=O)[O-])cc23)cc1

Procedure:
2-(4-tert-butylphenyl) ethanol (1.0 g, 5.59 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (48.5 mg, 2.02 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 6-Nitro-4-chloroquinazoline (1.17 g, 5.6 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[I-].C[S+](C)(C)=O.[CH:13]1([S:16][C:17]([F:29])([F:28])[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:19])[CH2:15][CH2:14]1>O1CCCC1>[CH:13]1([S:16][C:17]([F:29])([F:28])[C:18]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH2:3][O:19]2)[CH2:15][CH2:14]1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)SC1CC1
Reactant: CS(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: Fc1ccc(C2(C(F)(F)SC3CC3)CO2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A suspension of 60% sodium hydride (1.0 g, 0.025 mol) in tetrahydrofuran (50 ml)—dimethylsulfoxide (70 ml) was heated to an external temperature of 50° C., followed by the addition of trimethylsulfoxonium iodide (5.6 g, 0.025 mol) in portions. After stirring at the same temperature for one hour, the reaction mixture was cooled to −20° C. and added dropwise with a solution of 2-cyclopropylthio-2,2,2′,4′-tetrafluoroacetophenone (5.6 g, 0.021 mol) in tetrahydrofuran (20 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, followed by extraction with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 2-[(cyclopropylthio)(difluoro)methyl]-2-(2,4-difluorophenyl)oxirane (5.0 g, yield: 86%) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:20](=[O:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(NCCc2cccc(OC)c2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(N(CCc2cccc(OC)c2)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
(4-Methoxy-phenyl)-[2-(3-methoxy-phenyl)-ethyl]-amine (3.87 mmol) and acetyl chloride (4.26 mmol) were reacted ethyl acetate (50 mL). After 18 hours, the reaction was poured into ice (150 mL) and the organic extract was dried over sodium sulfate, filtered through celite and concentrated. The title compound (0.60 g) was obtained after silica gel chromatography (eluant: gradient from 10% to 40% ethyl acetate-hexane); MS: 300.4 (MH+); HPLC tR: 2.65 min; TLC Rf: 0.19 (ethyl acetate-hexane 2:3).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12](=[O:23])[NH:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31]C)=[O:29].Cl>CN(C)C=O>[CH3:31][O:30][C:28]([CH2:27][N:11]1[C:10]2[C:15](=[CH:16][C:17]([C:18]([F:21])([F:20])[F:19])=[C:8]([N:3]3[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]3[CH3:1])[CH:9]=2)[NH:14][C:13](=[O:22])[C:12]1=[O:23])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
2.2 g (6.8 mmol) of 6-(2,5-dimethyl-1-pyrrolyl)-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 11) were dissolved in 25 ml of anhydrous dimethylformamide under nitrogen and 0.245 g (8.2 mmol) of 80% sodium hydride was added a little at a time. The mixture was stirred at room temperature for 1 hour and then the solution was cooled to -25° C., and 1.4 g (8.9 mmol) of ethyl bromoacetate dissolved in 3 ml of dimethylformamide were added dropwise. The mixture was stirred for 90 minutes and then poured onto ice, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated in a rotary evaporator. The residue was purified by chromatography on silica gel (mobile phase: n-heptane/ethyl acetate=2/1), resulting in 0.8 g (30%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27]C(=O)CC1C2C(=CC=C(OC)C=2)N(CC2C=NC=CC=2)C=1C)C.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH3:25][OH:27]
Reactant: CCOC(=O)Cc1c(C)n(Cc2cccnc2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1cccnc1
Agent: NN
Product: CO
Yield: 17 %

Procedure:
5-Methoxy-2-methyl-1-[(3-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide. Using the method described in Example 1, Part G, 340 mg (1.0 mmol) of 5-methoxy-2-methyl-1-[(3-pyridyl)methyl]-1H-indole-3-acetic acid ethyl ester was reacted with 1.0 mL of hydrazine to give on crystallization from MeOH 54 mg (17% yield) of 5-methoxy-2-methyl-1-[(3-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide, mp 153°-154.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:21]=1[N+:37]([O-:39])=[O:38]>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:20]2[C:21]([N+:37]([O-:39])=[O:38])=[C:22]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[N:23]=[CH:24][N:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 mmol, 230 μL) and sodium hydride (1.0 mmol, 26 mg) were dissolved in dimethyl acetamide (1.0 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.21 mmol, 70 mg) was added. The reaction was stirred at 70° C. for 20 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 40/60 EtoAc/Hexanes) provided Compound A14 as a yellow oil (90 mg, 82%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.26 (s, 1H), 8.40 (s, 1H), 7.98 (d, 2H), 7.86 (d, 2H), 4.51 (t, 2H), 4.09 (m, 2H), 3.73 (t, 2H), 3.07 (s, 3H), 2.72 (m, 2H), 1.76 (m, 1H), 1.55 (q, 2H), 1.46 (s, 9H), 1.15 (m, 2H). LCMS (ESI), m/z 422.2 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:61]1([CH:67]([NH2:71])[CH2:68][CH2:69][CH3:70])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([NH:71][CH:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:68][CH2:69][CH3:70])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCCC(N)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC(Nc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a degassed solution of 3,5-dibromopyridine (0.4 g, 1.7 mmol), sodium tert-butoxide (227 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (145 mg, 0.09 mmol) and rac-BINAP (105 mg, 0.2 mmol) in dry toluene (10 mL) was added 1-phenylbutan-1-amine (0.2 mL). The mixture was heated at reflux for 24 h and upon cooling to room temperature was diluted with ether and washed with brine (3×30 mL). The solution was dried (Na2SO4) and concentrated and the residue chromatographed using ethyl acetate-hexane (40:60) as eluant. From the early fractions 97 mg of pure product was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40 ml of DMSO 3.7 g of 4-tert.-butylbenzene sulfonamide potassium salt was added. The resulting solution was stirred for 20 h at room temperature. Eventually, the mixture was poured onto 400 ml of water and washed twice with 200 ml of diethyl ether. The organic layers was extracted with 200 ml of water. The combinded aqueous layers was acidified with conc. hydrochloric acid. The mixture was cooled to 0° C. and 100 ml of brine was added. The precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.80 min, [M+1]+=448.17, [M−1]−=446.21.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10]1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[CH:10]1
Reactant: OCc1ccsc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccsc2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 102.5 %

Procedure:
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 228 mg of 3-thiophenemethanol were dissolved, and added 0.084 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 0.5 hours and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 500 mg of 5-(3-thienyl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:5][C:4]=1[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
0.59 g of ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzoyl]amino}methyl)benzyl]butanoate was dissolved in 5 ml ethanol, and 2 ml of 1 N sodium hydroxide was added, and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.50 g of 2-[4-methoxy-3-({[4-(trifluoromethyl)benzoyl]amino}methyl]benzyl]butanoic acid.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[N:7]([CH:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH2:6][C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[NH:3]1>[Pd]>[O:25]=[S:2]1(=[O:1])[N:7]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:6][C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[NH:3]1
Reactant: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Product: O=S1(=O)Nc2ccccc2CN1C1CCNCC1

Procedure:
Prepared analogously to Example A3f) from 3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine by catalytic hydrogenation in the presence of palladium/charcoal in a quantitative yield. Colourless, amorphous substance.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][C:17]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:19]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCc1cccs1)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 62.8 %

Procedure:
Chlorosulfonic acid (20.1 ml, 198 mmol) in CH2Cl2 (80 ml) was added dropwise to a solution of (63a) (10 g, 40 mmol) in CH2Cl2 (500 ml) at −80° C. The mixture was allowed to reach room temperature in 5 h. The reaction mixture was poured on ice and quickly extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was evaporated to dryness which afforded 8.8 g (63%) of desired sulfonyl chloride (63b); mp 133-35° C., 1H NMR (DMSO-d6) δ 9.21 (t, J=6.4 Hz, 1H), 7.87 (d, J=8.67 Hz, 2H), 7.53 (d, J=8.67 Hz, 2H), 6.91 (d, J=3.39 Hz, 1H), 6.77 (d, J=3.39 Hz, 1H), 4.53 (d, J=3.77 Hz, 2H).