Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[CH:22]([C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)=[CH2:23].C(O)(=O)C.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:22][C:24]2[CH:33]=[N:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: COc1ccc2nccc(NC(=O)C3CCNCC3)c2n1
Reactant: C=Cc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2nccc(NC(=O)C3CCN(CCc4cnc5ccccc5n4)CC3)c2n1
Yield: 12.9 %

Procedure:
A mixture of amine (1f) (0.403 g, 1.4 mmol), 2-vinyl-quinoxaline (b), (0.22 g, 1.4 mmol), acetic acid (0.1 ml) and ethanol (5.2 ml) was heated under reflux for 6 hours. The mixture was then made basic with aqueous sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with dichloromethane-methanol (99-1). After evaporation the residue was triturated with a small amount of ethyl acetate and crystallised. The solid was collected by filtration and dried to give the title compound (80 mg) mp.: 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid (5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)[CH3:17].O1CCOCC1>C(O)(=O)C>[N:22]1[CH:23]=[CH:24][C:19]([C:16](=[N:9][NH:8][C:6](=[O:7])[CH2:5][O:4][C:3]2[CH:10]=[C:11]([Cl:15])[C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[CH3:17])=[CH:20][CH:21]=1
Reactant: NNC(=O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)c1ccncc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=NNC(=O)COc1cc(Cl)c(Cl)cc1Cl)c1ccncc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A solution of 5.39 gm (0.02 mole) of 2,4,5-trichlorophenoxyacetic acid hydrazide, 2.42 gm (0.02 mole) of 4-acetylpyridine, 125 ml of dioxane and 2 ml of acetic acid is refluxed 4 hr. The hot solution is filtered. The filtrate is diluted with water until cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected to yield 6.24 gm (83%) of the title compound having a melting point of 227.4° C. (decomp).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[O:29][C:28]([C:31]([NH:33][C@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:32])=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C1COCC1>CN(C=O)C>[ClH:12].[N:36]12[CH2:37][CH2:38][CH:39]([CH2:40][CH2:41]1)[C@H:34]([NH:33][C:31]([C:28]1[O:29][C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][NH:14][C:10]([NH:9][CH3:8])=[O:11])=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=1)=[O:32])[CH2:35]2
Reactant: NCc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)oc12
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)oc12
Reaction time: 18 h

Procedure:
36 μl (0.26 mmol) of triethylamine and 29.5 μl (0.52 mmol) of methyl isocyanate are added to a solution of 57.9 mg (0.13 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride (Example 174) in 0.7 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 49.2 mg (81.2% of theory) of the title compound are obtained.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N-]>C(O)C>[CH2:9]([O:12][CH:3]([O:14][CH2:4][CH3:3])[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:8]
Reactant: COc1ccc(CC(=O)C=[N+]=[N-])cc1
Solvent: CCO
Product: CCOC(OCC)C(=O)Cc1ccc(OC)cc1
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 1-diazo-3-(4-methoxyphenyl)propan-2-one (62) (477 mg, 2.51 mmol) was dissolved in anhydrous ethanol (5 mL) and cooled to 0° C. To this was added tert-butyl hydochloride (285 μL, 2.52 mmol) and stirred for an hour at the same temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=10/1) to give 1,1-diethoxy-3-(4-methoxyphenyl)propan-2-one (63) as a colorless oily substance (357 mg, 1.41 mmol, 56.4%).
Reaction SMILES: O.O.[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11])[N:8]=1.N12CCN(CC1)CC2.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[S:27]>CC(N(C)C)=O>[CH2:29]([O:28][P:26]([O:11][C:10](=[O:12])/[C:9](/[C:7]1[N:8]=[C:4]([NH2:3])[S:5][CH:6]=1)=[N:13]\[O:14][C:15](=[O:17])[CH3:16])([O:31][CH2:32][CH3:33])=[S:27])[CH3:30]
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC(C)=O)c1csc(N)n1
Temperature: -20 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of 134.9 g (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid dihydrate (508.6 mmol) and 570 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.09 mmol) in 1500 ml dimethylacetamide was added under argon 158 ml tributylamine (661 mmol). The yellowish solution was cooled to -20° C. and over 30 min was added dropwise 104 ml diethyl chlorothiophosphate (661 mmol). Stirring was continued at -20° C. for 3.5 h. The reaction was followed by HPLC. After 3 h, all starting material was consumed. The reaction mixture was allowed to warm up to 0° C. and over 1.0 h was added dropwise 2200 ml water. The precipitated product was filtered, washed with water and dissolved in 800 ml dichloromethane. The aqueous layer was back-extracted with 300 ml dichloromethane. The combined organic layers were dried over 70 g sodium sulfate and concentrated under reduced pressure until the product started to crystallize. The residual solution was cooled to 2° C. and 1200 ml n-hexane was added dropwise over 1 h. The resulting suspension was stirred for 1 h at 2° C. and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxythiophosphoryl ester was obtained as a white solid (166.9 g, yield=86%, mp 128°-130° C. and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Br.O>O1CCCC1>[CH3:21][O:22][CH2:23][N:11]([CH2:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1.00 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.22 g of 60% sodium hydride at room temperature for 30 minutes. 0.78 g of methoxymethyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.90 g of methyl N-methoxymethyl-N-(3-phenylbenzyl)carbamate as a pale yellow transparent viscous liquid.
Reaction SMILES: CCC([O:5][C@@H:6]1[C@:28]2([CH3:30])[O:29][C@H:27]2[C@H:26]([CH3:31])[C@H:25]2[O:32][C:33]([NH:35][C@:23]([OH:36])([CH2:24]2)[C@H:22]([O:37][CH3:38])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:39])[CH2:17][C:15]2=[CH:16][C:11](=[C:12]([Cl:42])[C:13]([O:40][CH3:41])=[CH:14]2)[N:10]([CH3:43])[C:8](=[O:9])[CH2:7]1)=[O:34])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:31][CH:26]1[CH:27]2[O:29][C:28]2([CH3:30])[CH:6]([OH:5])[CH2:7][C:8](=[O:9])[N:10]([CH3:43])[C:11]2=[C:12]([Cl:42])[C:13]([O:40][CH3:41])=[CH:14][C:15](=[CH:16]2)[CH2:17][C:18]([CH3:39])=[CH:19][CH:20]=[CH:21][CH:22]([O:37][CH3:38])[C:23]2([OH:36])[NH:35][C:33]([O:32][CH:25]1[CH2:24]2)=[O:34]
Reactant: CCC(=O)O[C@H]1CC(=O)N(C)c2cc(cc(OC)c2Cl)CC(C)=CC=C[C@@H](OC)[C@@]2(O)C[C@H](OC(=O)N2)[C@@H](C)[C@@H]2O[C@@]12C
Agent: CCC(=O)O[C@H]1CC(=O)N(C)c2cc(cc(OC)c2Cl)C/C(C)=C/C=C/[C@@H](OC)[C@@]2(O)C[C@H](OC(=O)N2)[C@@H](C)[C@@H]2O[C@@]12C
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -50 °C
Reaction time: 2 h

Procedure:
In 800 ml of anhydrous tetrahydrofuran (THF) is dissolved 15.0 g of antibiotic Ansamitocin mixture (12% of Ansamitocin P-2, 71% of P-3 and 17% of P-4) and, under dry nitrogen gas streams, the solution is cooled to -50° C. in a dry ice-ethanol bath. Then, 13.0 g of lithium aluminum hydride (LAH) is added at one stroke and the mixture is stirred at a temperature from -50° C. to -22° C. for 2 hours. Then, at -28° C., a further 3 g of LAH is added and the reaction mixture is stirred at -28° C. to -22° C. for 80 minutes. Thereafter, at -50° C., 750 ml of 2 N HCl is added dropwise with caution and the reaction mixture is extracted three times with 2.6 l, 1.6 l and 0.8 l portions of ethyl acetate. The extracts are pooled, washed twice with a 100 ml each portion of saturated aqueous solution of sodium chloride and dried (MgSO4 , 250 g). The solvent is distilled off under reduced pressure and the residue (13.6 g) is chromatographed on a column of silica gel (1.2 kg), elution being carried out with ethyl acetate-water (98.5:1.5, V/V). The eluate is collected in 400-gram fractions. Fractions 35 through 52 are pooled, the solvent distilled off and the residue dried in vacuo to obtain 7.25 g of maytansinol. Then, fractions 53 through 68 are similarly treated to obtain 1.55 g of a substantially equimolar mixture of maytansinol and dechloromaytansinol. Similarly, fractions 69 through 86 yield 0.78 g of dechloromaytansinol.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: COc1ccccc1N=C=O
Product: COc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 27 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate (1 mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg, 27%). EI-MS m/z 302 (M−H)−
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:7]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:7]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([CH:11]=1)[C:5]([OH:31])=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Yield: 88 %

Procedure:
Sodium hydroxide hydrolysis of 5-(decyloxy)-2-(phenylmethoxy) benzoic acid methyl ester under conditions described in Example 60 gave 5-(decyloxy)-2-(phenylmethoxy)benzoic acid (88% yield, mp 63°-65°).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH:35]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH:35]1([NH:40][CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]5[S:28][CH:29]=[CH:30][CH:31]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC1CCCC1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCNC4CCCC4)CC3)c[nH]c12
Yield: 31.1 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (0.09 mmol) and cyclopentanamine (0.04 mL, 0.45 mmol) were allowed to react in the presence of K2CO3 (44 mg, 0.45 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (14 mg, 39%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[N:11][C:12]([NH2:13])=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[N:5]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:13][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:27]#[N:28])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:7]=12
Reactant: NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 1-(2-aminoethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (287 mg, 0.829 mmole), 2-cyanoacetic acid (85 mg, 1.0 mmole) and TEA (0.14 ml, 1.0 mmole) in DMF (10 mL) was added HATU (347 mg, 0.912 mmole). After stirring 3 hr at room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with aq. NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated. The resulting residue was subjected to column chromatography (3% MeOH/DCM) to provide 90 mg (22% yield from step 1) of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyanoacetamide.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][C:15]=3[C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[CH3:17][C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][C:12]=1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2oc3ccc(Cl)cc3c2C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)c2ccc(=O)[nH]n2)oc2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-pyridazine (0.5 mmol, 162 mg), conc. HCl (1 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue. The resulting yellow precipitate was collected and crystallized from ethanol to obtain the desired product: 6-(3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one (73%, 113 mg); mp 247° C.-248° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][CH2:36][OH:37].[Na+].[I-]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([N:18]([CH2:35][CH2:36][OH:37])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCOc2cccc(N(CCO)S(=O)(=O)c3ccccc3)c2)cc1
Yield: 45.2 %

Procedure:
N-{3-[2-(4-cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.093 g; 0.246 mmol; from Example 1(iv) above), K2CO3 (0.047 g, 0.34 mmol), 2-chloroethanol (0.028 g; 0.34 mmol) and NaI (0.052 g; 0.34 mmol) were stirred in DMF (4 mL) for 24 hours at 100° C. The solvent was removed in vacuo. The residue was dissolved in water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried (Na2SO4) and the solvent evaporated. Purification by flash chromatography (SiO2; toluene:EtOAc 10:0, 9:1, 8:2, 6:4) afforded 0.047 g (45%) of the sub-title compound.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH:17]([N:19]2[CH2:30][CH:22]3[C:23]4[CH:24]=[CH:25][S:26][C:27]=4[C:28](=O)[CH:21]3[CH2:20]2)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.ClCCl>[CH2:1]=[C:28]1[C:27]2[S:26][CH:25]=[CH:24][C:23]=2[CH:22]2[CH2:30][N:19]([CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:18])[CH2:20][CH:21]12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(c1ccccc1)N1CC2C(=O)c3sccc3C2C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1c2sccc2C2CN(C(C)c3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Potassium bis(trimethylsilyl)amide (308 mg, 1.55 mmol) was added to a solution of methyl triphenylphosphonium bromide (575 mg, 1.61 mmol) in 7 mL of THF at 0° C. After 30 minutes of stirring at 0° C., the product from step e) (303 mg, 1.07 mmol) dissolved in 2 mL of THF was added to the reaction mixture and was allowed to come to room temperature over 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and was washed with brine, dried (MgSO4) and concentrated to an oil. The crude was purified by column chromatography (SiO2) using 5-55% ethylacetate-hexane gradient to afford the subtitle compound (226 mg, yield: 74.8%). MS calculated for C18H19NS +H: 282, observed: 282.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:35])[CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:37][C:38]1[C:43]([C:44]([OH:46])=O)=[C:42]([CH3:47])[N:41]=[CH:40][N:39]=1>>[CH2:18]([N:17]([CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:44]([C:43]2[C:38]([CH3:37])=[N:39][CH:40]=[N:41][C:42]=2[CH3:47])=[O:46])[CH2:27][CH2:26]1)[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(Cc2ccc(N(Cc3ccccc3)C3CCN(C(C)CCN)CC3)cc2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccccc2)c2ccc(Cc3ccc(C(=O)O)cc3)cc2)CC1
Yield: 60.9 %

Procedure:
Using general procedure E with 4-(4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzyl)-benzoic acid methyl ester (see EXAMPLE 100) (79 mg, 0.16 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (30 mg, 0.20 mmol) followed by general procedure K with the resulting ester gave COMPOUND 102 as a yellow powder (59 mg, 70% over 2 steps). 1H NMR (CDCl3+CD3OD) δ 1.20 (d, 3H, J=6.0 Hz), 1.68 (m, 1H), 1.90 (m, 4H), 2.13 (m, 1H), 2.40 (s, 6H), 2.61 (m, 1H), 2.81 (m, 1H), 3.09-3.37 (m, 4H), 3.54 (m, 1H), 3.80 (m, 3H), 4.23 (s, 2H), 6.55 (d, 2H, J=7.8 Hz), 6.90 (d, 2H, J=7.8 Hz), 7.09 (m, 7H), 7.71 (d, 2H, J=7.5 Hz), 8.77 (s, 1H). 1H NMR (CDCl3+CD3OD) δ 12.71, 21.99, 27.18, 27.54, 31.62, 37.35, 41.10, 45.34, 50.14, 51.13, 54.40, 58.93, 114.26, 126.48, 126.91, 128.73, 128.87, 129.96, 130.02, 130.82, 131.69, 140.33, 146.24, 147.43, 157.34, 163.70, 167.59, 172.17. ES-MS m/z 606 (M+H). Anal. Calcd. for C37H43N5O3.0.7CH2Cl2: C, 68.07; H, 6.73; N, 10.53. Found. C, 68.09; H, 6.66; N, 10.49.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:41]CCI>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13]([I:41])=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: ICCI
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(I)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
Under argon, 230 mg (0.493 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were dissolved in 15 ml of THF and cooled to −78° C. At this temperature, 1.182 ml (1.182 mmol) of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in THF) were added dropwise. After 1 h of stirring at −78° C., a solution of 0.143 ml (1.084 mmol) of 1,2-diiodethane in 5 ml of THF was added dropwise, and the reaction mixture was stirred at −78° C. for a further hour. The reaction was terminated by addition of 20 ml of 10% strength aqueous sodium thiosulfate solution. After the mixture had warmed to room temperature, the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase A=water, B=acetonitrile; gradient: 0.0 min 10% B, 30 min 95% B, 34 min 95% B, 34.01 min 10% B, 38 min 10% B; flow rate: 50 ml/min; +0.1% TFA). The solid which had precipitated from the acetonitrile/water mixture was filtered off and dried under high vacuum. This gave 60 mg of the target compound in a purity of 76% (yield: 15% of theory).