Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[Br:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: Nc1ccc(Br)cc1Br
Agent: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1Br

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2 -aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2,4-dibromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4[N:17]([N:29]=[CH:30]N=4)[C:18]([C:21]4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:45][C:44]=2[F:55])=[N:35][CH:34]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:55][C:44]1[CH:45]=[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH:47]=[CH:48][C:43]=1[NH:42][C:36]1[C:37]2[N:38]([N:39]=[CH:40][N:41]=2)[C:33]([C:21]2[CH:30]=[N:29][NH:17][CH:18]=2)=[CH:34][N:35]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: Fc1cc(N2CCOCC2)ccc1Nc1ncc(Br)n2ncnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Fc1cc(N2CCOCC2)ccc1Nc1ncc(-c2cn[nH]c2)n2ncnc12
Yield: 38 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(2-fluoro-4-morpholin-4-yl-phenyl)-amine (80 mg, 0.203 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (79 mg, 0.406 mmol), and Pd(PPh3)4 (59 mg, 0.051 mmol) in 1.5N Na2CO3 (1.09 mL, 1.62 mmol) and dioxane (3.25 mL). The reaction mixture is purified by silica gel column chromatography eluting with 97:3 DCM:NH3 (7M in MeOH). The fractions containing the product are combined and evaporated in vacuo to afford a solid which is triturated with diethyl ether and petroleum ether to yield the title compound (29 mg, 38%). LCMS: Rt 2.90 min (96%).
Reaction SMILES: COC(C1SC(C#CC(C)(C)C)=CC=1NC1CC(OCC2C=CC=CC=2)C1)=O.C(N(CC)C(C)C)(C)C.C[C@H]1CC[C@H](C(Cl)=O)CC1.[CH3:48][O:49][C:50]([C:52]1[S:53][C:54]([C:79]#[C:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[CH:55][C:56]=1[N:57]([CH:67]1[CH2:70][CH:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:68]1)[C:58]([C@H:60]1[CH2:65][CH2:64][C@H:63]([CH3:66])[CH2:62][CH2:61]1)=[O:59])=[O:51]>ClCCCl>[CH3:48][O:49][C:50]([C:52]1[S:53][C:54]([C:79]#[C:80][C:81]([CH3:82])([CH3:84])[CH3:83])=[CH:55][C:56]=1[N:57]([CH:67]1[CH2:70][CH:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[CH2:68]1)[C:58]([C@H:60]1[CH2:65][CH2:64][C@@H:63]([CH3:66])[CH2:62][CH2:61]1)=[O:59])=[O:51]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CC(OCc2ccccc2)C1
Agent: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CC(OCc2ccccc2)C1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@@H](C)CC1)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(3-benzyloxy-cyclobutylamino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.26 g, 3.17 mmol) and N,N-diisopropylethylamine (2.4 mL, 13.8 mmol) in DCE (8 mL) was treated with trans-4-methyl-cyclohexanecarbonyl chloride and heated to 100 deg C. for 5 hours. The reaction mixture was cooled to room temperature, adsorbed onto silica, and purified by silica gel chromatography (0-30% ethyl acetate:hexanes). This resulted in 590 mg (36% yield) of cis-cyclobutyl isomer (cis-3-[(3-benzyloxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester) and 230 mg (14% yield) of the trans-cyclobutyl isomer (trans-3-[(3-benzyloxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([OH:25])[CH3:24])=[CH:19][C:18]=2[I:26])=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]>ClCCl.[O-2].[O-2].[Mn+4]>[F:33][C:2]([F:1])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=2[I:26])=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C(C)O)cc1I
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C(C)=O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
1-(4-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-3-iodophenyl)ethanol (26 mg, 0.0446 mmol) was dissolved in dichloromethane (3 mL). The resultant mixture was added with manganese dioxide (78 mg, 0.891 mmol) at room temperature, and stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered using celite and concentrated in vacuum, and 1-(4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-3-iodophenyl) ethanone (16 mg, yield 60%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:8][NH2:9].[CH2:11]([N:13]1[C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12].C(Cl)(=O)C(Cl)=O>>[CH2:11]([N:13]1[C:17]([C:18]([NH:9][NH:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[S:10])=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12]
Reactant: CCn1nc(C)cc1C(=O)Cl
Reactant: COCCCNC(=S)NN
Agent: O=C(Cl)C(=O)Cl
Product: CCn1nc(C)cc1C(=O)NNC(=S)NCCCOC

Procedure:
The title compound was synthesized in a manner similar to that described in Example 1. 3-Methoxy-n-propyl isothiocyanate was prepared from 3-methoxy-n-propylamine and thiophosgene at high temperature and then reacted with hydrazine in pyridine to give the intermediate 4-(3-methoxy-n-propyl)-3-thiosemicarbazide. 4-(3-Methoxy-n-propyl)-3-thiosemicarbazide (1.64 g) was reacted with 1-ethyl-3-methylpyrazole-5-carboxylic acid chloride (1.73 g, prepared from the acid and oxalyl chloride) to give 2 g of 1-(1ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide. Treatment of 1-(1-ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide with potassium hydroxide in ethanol gave 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole. Reaction of the sodium salt of 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole(0.73 g) with 2-bromo-5-nitrothiazole (0.52 g) yielded crude 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole as in Example 1. Crystallization from ethanol and water gave 0.3 g of 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:17])[NH:9][N:10]2[C:14]([CH3:15])=NN=[C:11]2[CH3:16])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:20])C>>[C:14]([N:10]1[C:11]([CH3:16])=[N:17][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:20])[CH3:15]
Reactant: Cc1nnc(C)n1NC(=N)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1nc(-c2ccc(Cl)cc2)nc1C

Procedure:
63.6 g (254.0 mM) 4-Chloro-N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)benzenecarboximidamide prepared in part B and 67 ml of acetic anhydride in a 300 ml round bottom flask equipped with a distillation head are heated to 170° in an oil bath. A solution forms from which acetic acid distills off in the first few minutes. The mixture is refluxed for 2.5 hours and the excess acetic anhydride is evaporated to dryness under vacuum to produce a residue comprising a mixture of the title compound and its 1-acetyl-5-(4-chlorophenyl)-3-methyl isomer. The residue is triturated with 120 ml of water at room temperature and filtered. The filter cake is dissolved in 1 liter of hot ethanol, filtered hot, and the product precipitated from the hot alcohol by adding 3 liters of cold water. The product is filtered off, wshed with water, and dried at 80° under vacuum to yield 37.6 g of the 1-acetyl-3-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole as a crystalline material (99% pure), m.p. 132°-133°.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:35])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:35][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 451.55 [M+H]+; tR=1.55 min (System 3).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Ic1cccs1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccs2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-iodothiophene. The title compound was obtained in 51% yield as light brown foam. MS (m/e): 488.4 (MH+, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO.CN(C=O)C>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Racemic cis-1-amino-2-indanol (66.6 g, water wet, content 81.1%) was dissolved in 180 ml of methanol with 10 ml of DMF at reflux. Then 65 g of (R,R)-tartaric acid dissolved in 200 ml of methanol were added. Stirring of the mixture was continued for one hour at reflux and then it was cooled down again to 20° C. and isolation by filtration was effected. The solid was washed twice with 120 ml of methanol. After drying, 54.8 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 97.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH2:11].[C:12](=S)=[S:13]>O1CCCC1>[F:10][C:4]1[C:3]2[NH:11][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: S=C=S
Reactant: Nc1cc(F)c(F)c(F)c1N
Solvent: C1CCOC1
Product: Fc1cc2[nH]c(=S)[nH]c2c(F)c1F
Temperature: 25 °C
Yield: 22.9 %

Procedure:
To a solution of 1,2-diamino-3,4,5-trifluoro-benzene (2.5 g, 15.4 mmol) in 20 mL of tetrahydrofuran under argon, are added 2.3 mL (38.6 mmol) of carbon disulfide. The reaction mixture is heated at reflux temperature for 3 h, upon which 2.3 mL (38.6 mmol) of carbon disulfide are added and reflux is maintained for 16 h. Carbon disulfide 2.3 mL (38.6 mmol) is added and reflux is maintained for 8 h, upon which 2.3 mL (38.6 mmol) of carbon disulfide are added and reflux is maintained for 16 h. The reaction mixture is then cooled to room temperature and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: cyclohexane/ethyl acetate 90/10 v/v; rate: 35 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol 100/0, then 98/2 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.72 g of 4,5,6-trifluoro-1,3-dihydro-benzimidazole-2-thione is obtained as an off-white solid. LCMS-DAD-ELSD: 203(−): [M−H]−; 205(+): [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Reaction time: 3 h

Procedure:
350 mg of 10% palladium/carbon were added to a solution of 3.5 g (9.18 mmol) of 8-(benzyloxy)-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 250 ml of ethyl acetate, and hydrogen was applied at room temperature and atmospheric pressure. After 3 h, the mixture was filtered off through kieselguhr, the filter cake was washed intensively with ethyl acetate/methanol and the filtrate was evaporated to dryness. Methyl tert-butyl ether was added to the crude product obtained, the product was triturated and the solid was then filtered off and dried at 40° C. under high vacuum. This gave 2.1 g (79% of theory) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][NH:9][C:10]2[N:15]=[C:14]([CH3:16])[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:19]=3)=[CH:12][CH:11]=2)C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[NH:9]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:19]=2)=[CH:12][CH:11]=1)[NH2:8]
Reactant: Cc1nc(NN=C(c2ccccc2)c2ccccc2)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
6-(2-(Diphenylmethylene)hydrazinyl)-2-methyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (9.3 g, 20.19 mmol) was dissolved in toluene (497 mL). Concentrated HCl (134 mL, 1608 mmol) was added and the reaction mixture was stirred for 1.5 h at 110° C., allowed to cool to RT, and stirred for 10 h. The organic phase was removed and the aqueous phase was extracted with toluene (1×100 mL). The combined organics were back extracted with 1 N HCl (1×100 mL). The combined aqueous phases were adjusted to pH ˜11 with 50% NaOH (aq), saturated with solid NaCl, and extracted with EtOAc (3×200 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 6-hydrazinyl-2-methyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (4.7 g, 79%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.49 (dd, J=5.7, 2.4 Hz, 1H), 4.14 (s, 2H), 3.84 (s, 3H), 2.11 (s, 3H); MS (ESI) m/z: 297.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[F:55]C1C=CC=CC=1C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:55])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Fc1ccccc1C[Zn+]
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Fc1ccccc1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 77 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (2-fluorobenzyl)zinc(II) chloride in 77% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:35][OH:36].C(N(CC)CC)C>C(O)C>[NH2:2][C:1](=[N:35][OH:36])[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C#N)cc2)C1=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(N)=NO)cc2)C1=O)c1ccccc1

Procedure:
b 120 l of ethanol were initially introduced into a vessel. At room temperature, 12 kg (26.786 mol) of ethyl (S)-3-(2-((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionate were added into the vessel, while stirring. 3.74 kg (53.813 mol) of hydroxylamine hydrochloride and 5.44 kg (7.45 l; 53.86 mol) of triethylamine were added. The reaction mixture was heated to reflux and stirred at 80° C. for 2 h. 90 l of ethanol were distilled off in vacuo at a bath temperature of 50° C. The remaining mixture was taken up in 220 l of ethyl acetate and this latter mixture was extracted three times with 50 l of water on each occasion. The ethyl acetate phase was evaporated down to 30 l in vacuo and at a bath temperature of 50° C. It was treated four times with 10 l of toluene on each occasion and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:12].CC(C)=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])=[CH:7][C:6]=1[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1ccc(N)cc1C
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 2-methyl-4-amino phenylacetic acid methyl ester (5.3 mmol) in acetone (10 mL) dry pyridine (7.95 mmol) and phenylsulfonyl chloride (6.36 mmol) have been added and the resulting solution has been left stirring overnight at room temperature. Acetone has been evaporated and the residue diluted with CHCl3 (15 mL), washed with 1N HCl (2×10 mL), water (3×20 mL), dried over Na2SO4 and evaporated under vacuum to give {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid methyl ester as colourless oil (5.0 mmol) pure to be used in the following reaction. Following the procedure described for Example 1 and starting from the methyl ester (5.0 mmol) pure {2-methyl-4-[(phenylsulphonyl)amino]phenyl}acetic acid has been synthesised (4.75 mmol).
Reaction SMILES: [C:1]1([O:7][C:8](=[NH:10])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:18]([NH:10][C:8](=[NH:9])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N=C(NC(=O)c1ccccc1)Oc1ccccc1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
O-phenylisourea (1 g) was dissolved in chloroform (50 ml) and triethylamine (1.2 g) and thereafter benzoylchloride (0.8 g) were added at 0° to 5° C. After stirring for one hour at 0° to 5° C., the mixture was washed with water and the chloroform was evaporated off under reduced pressure to give N-benzoyl-O-phenylisourea (1 g), m.p. 125.1° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Clc1nccc2ccccc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2[nH]c(C)c(-c3nccc4ccccc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 1-chloroisoquinoline.
Reaction SMILES: B(Br)(Br)[Br:2].Br.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]([O:25]C)[CH:16]=1>C(Cl)Cl>[BrH:2].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]([OH:25])[CH:16]=1
Reactant: COc1cc(C(=O)NCCCCCCN)cc([N+](=O)[O-])c1O
Reactant: BrB(Br)Br
Agent: Br
Solvent: ClCCl
Product: NCCCCCCNC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.25 g of boron tribromide are added -20° to a suspension of 392.3 mg of N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamide hydrobromide in 25 ml of dry methylene chloride. After the addition the mixture is stirred at -20° for 1 hour and subsequently at room temperature for 17 hours. The reaction mixture is then evaporated, the residue is treated with 10 ml of water and stirred at room temperature for 1 hour. After evaporating the water the residue is chromatographed on Sephadex LH 20 with toluene/ethanol (1:1). There is obtained N-6-aminohexyl-3,4-dihydroxy-5-nitrobenzamide hydrobromide of m.p. 205°-207° (from ethanol).